Methods and compositions for preventing opioid abuse

ABSTRACT

Abuse-resistant opioid compounds, drug delivery systems, pharmaceutical compositions comprising an opioid covalently bound to a chemical moiety are provided. Methods of delivering an active ingredient to a subject and methods of preventing opioid abuse are also provided.

FIELD OF THE INVENTION

The following invention generally relates to the field of preventing theoveruse and/or abuse of certain medicines, and in particular, opioidcompounds.

BACKGROUND OF THE INVENTION

Opioids reduce pain by decreasing perception of pain, decreasingreaction to pain, and increasing pain tolerance. They have long beenused in the treatment of acute and chronic pain. Opioid use may produceside effects such as feelings of euphoria, and, as such, opioids areamong the most misused and abused medications. Attempts to createabuse-resistant opioids have been made (e.g., crush-resistantformulations), but skilled illicit chemists have thus far been able toextract the opioids from these formulations.

Therefore there at least remains a need in the art for the availabilityof new methods and compositions for preventing opioid abuse.

SUMMARY OF THE INVENTION

One or more embodiments of the invention may address one or more of theaforementioned problems. The present invention addresses some of theneeds mentioned above by using abuse-resistant opioid compoundscomprising an opioid covalently bound to a chemical moiety. For example,certain embodiments according to the present invention provideabuse-resistant opioid compounds. In some embodiments, theabuse-resistant opioid compound may comprise an opioid covalently boundto a chemical moiety.

In another aspect, the present invention provides a drug delivery systemincluding abuse-resistant opioid compounds. In such embodiments, theabuse-resistant opioid compound comprises an opioid covalently bound toa chemical moiety.

In another aspect, the present invention provides a pharmaceuticalcomposition including abuse-resistant opioid compounds wherein theabuse-resistant opioid compounds comprise an opioid covalently bound toa chemical moiety.

In another aspect, the present invention provides a method of deliveringan active ingredient to a subject by administering a therapeuticallyeffective amount of an opioid compound to a subject.

In another aspect, the present invention provides a method of preventingopioid abuse by administering a therapeutically effective amount of anopioid compound to a subject.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention now will be described more fully hereinafter withreference to the accompanying drawings, in which some, but not allembodiments of the invention are shown. The present invention may beembodied in many different forms and should not be construed as limitedto the embodiments set forth herein; rather, these embodiments areprovided so that this disclosure will satisfy applicable legalrequirements and demonstrate exemplary embodiments of the invention.Repeat use of reference characters in the present specification anddrawings is intended to represent same or analogous features or elementsof the invention.

FIG. 1 illustrates plasma concentrations of oxymorphone at dose 1.77mg/kg Oxymorphone HCl Oral for individual animals;

FIG. 2 illustrates mean and standard deviation plasma concentrations ofoxymorphone at dose 1.77 mg/kg Oxymorphone HCl Oral;

FIG. 3 illustrates plasma concentrations of oxymorphone at dose 3.54mg/kg Oxymorphone HCl Oral for individual animals;

FIG. 4 illustrates mean and standard deviation plasma concentrations ofoxymorphone at dose 3.54 mg/kg Oxymorphone HCl Oral;

FIG. 5 illustrates plasma concentrations of oxymorphone at dose 7.12mg/kg Oxymorphone Oleate (Ex No. B3) Oral for individual animals;

FIG. 6 illustrates mean and standard deviation plasma concentrations ofoxymorphone at dose 7.12 mg/kg Oxymorphone Oleate (Ex No. B3) Oral;

FIG. 7 illustrates plasma concentrations of oxymorphone at dose 5.56mg/kg Oxymorphone Malate (Ex No. B5) Oral for individual animals;

FIG. 8 illustrates mean and standard deviation plasma concentrations ofoxymorphone at dose 5.56 mg/kg Oxymorphone Malate (Ex No. B5) Oral;

FIG. 9 illustrates plasma concentrations of oxymorphone at dose 6.72mg/kg Oxymorphone Mandelate (Ex No. B1a) Oral for individual animals;

FIG. 10 illustrates mean and standard deviation plasma concentrations ofoxymorphone at dose 6.72 mg/kg Oxymorphone Mandelate (Ex No. B1a) Oral;

FIG. 11 illustrates plasma concentrations of oxymorphone at dose 5.48mg/kg Oxymorphone Mandelate (Ex No. B1b) Oral for individual animals;

FIG. 12 illustrates mean and standard deviation plasma concentrations ofoxymorphone at dose 5.48 mg/kg Oxymorphone Mandelate (Ex No. B1b) Oral;

FIG. 13 illustrates plasma concentrations of oxymorphone at dose 6.01mg/kg Oxymorphone Lactate (Ex No. B2a) Oral for individual animals;

FIG. 14 illustrates mean and standard deviation plasma concentrations ofoxymorphone at dose 6.01 mg/kg Oxymorphone Lactate (Ex No. B2a) Oral;

FIG. 15 illustrates plasma concentrations of oxymorphone at dose 4.93mg/kg Oxymorphone Lactate (Ex No. B2b) Oral for individual animals;

FIG. 16 illustrates mean and standard deviation plasma concentrations ofoxymorphone at dose 4.93 mg/kg Oxymorphone Lactate (Ex No. B2b) Oral;

FIG. 17 illustrates plasma concentrations of oxymorphone at dose 7.4mg/kg Oxymorphone Stearate (Ex No. B4) Oral for individual animals;

FIG. 18 illustrates mean and standard deviation plasma concentrations ofoxymorphone at dose 7.4 mg/kg Oxymorphone Stearate (Ex No. B4) Oral;

FIG. 19 illustrates plasma concentrations of oxymorphone at dose 6.16mg/kg Oxymorphone Alanine (Ex No. B6) Oral;

FIG. 20 illustrates mean and standard deviation plasma concentrations ofoxymorphone at dose 6.16 mg/kg Oxymorphone Alanine (Ex No. B6) Oral;

FIG. 21 illustrates plasma concentrations of oxymorphone at dose 5.41mg/kg Oxymorphone Alanine (Ex No. B7) Oral;

FIG. 22 illustrates mean and standard deviation plasma concentrations ofoxymorphone at dose 5.41 mg/kg Oxymorphone Alanine (Ex No. B7) Oral;

FIG. 23 illustrates plasma concentrations of oxymorphone at dose 6.01mg/kg Oxymorphone Mandelate (Ex No. B8) Oral;

FIG. 24 illustrates mean and standard deviation plasma concentrations ofoxymorphone at dose 6.01 mg/kg Oxymorphone Mandelate (Ex No. B8) Oral;

FIG. 25 illustrates plasma concentrations of oxymorphone at dose 6.02mg/kg Oxymorphone Malate (Ex No. B9) Oral;

FIG. 26 illustrates mean and standard deviation plasma concentrations ofoxymorphone at dose 6.02 mg/kg Oxymorphone Malate (Ex No. B9) Oral; and

FIG. 27 illustrates average plasma concentrations of oxycodone in ratsat various doses of opioid compounds according to certain embodiments ofthe present invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Reference will now be made in detail to exemplary embodiments of theinvention, one or more examples of which are illustrated in theaccompanying drawings. Each example is provided by way of explanation ofthe invention, not limitation of the invention. In fact, it will beapparent to those skilled in the art that modifications and variationscan be made in the present invention without departing from the scope orspirit thereof. For instance, features illustrated or described as partof one embodiment may be used on another embodiment to yield a stillfurther embodiment. Thus, it is intended that the present inventioncovers such modifications and variations as come within the scope of theappended claims and their equivalents.

As used herein, the term “composition” may comprise any compositioncontaining one or more opioid compounds. The composition may comprise adry formulation, an aqueous solution, or a sterile composition.Compositions comprising the opioid compounds described herein may bestored in freeze-dried form and may be associated with a stabilizingagent such as a carbohydrate. In use, the composition may be deployed inan aqueous solution containing salts, e.g., NaCl, detergents such assodium dodecyl sulfate (SDS), and other components.

The term “alkyl”, as used herein, may refer to linear or branched alkylgroups. Exemplary alkyl groups include methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl,heptyl, octyl and the like. Unless otherwise specified, an alkyl grouptypically has from about 1 to about 10 carbon atoms.

The term “alkoxy”, as used herein, may refer to an —O (alkyl) group,where alkyl is as defined above. Exemplary alkyl groups include methoxy,ethoxy, propoxy, butoxy, iso-propoxy, iso-butoxy, and the like. Unlessotherwise specified, an alkoxy group typically has from 1 to about 10carbon atoms.

The term “amine”, as used herein, may refer to a primary, secondary, ortertiary amino group. The secondary and tertiary amine may containalkyl, cycloalkyl or aryl substitutions. Some examples of amines includeNH₂, NHMe, NMe₂, NH(cyclopropyl), and the like. Unless otherwisespecified, the alkyl or cycloalkyl group on an amine typically has from1 to about 8 carbon atoms.

The term “aryl”, as used herein, may refer to an optionally substitutedmonocyclic or polycyclic aromatic ring system of about 6 to about 14carbon atoms. Exemplary aryl groups include phenyl, naphthyl, and thelike. Unless otherwise specified, an aryl group typically has from 6 toabout 14 carbon atoms.

The term “salts”, as used herein, may refer to any acid or base salt,pharmaceutically acceptable solvates, or any complex of the compoundthat, when administered to a recipient, is capable of providing(directly or indirectly) a compound as described herein. It should beappreciated, however, that salts that are not pharmaceuticallyacceptable also lie within the scope of the invention. The preparationof salts can be carried out using known methods.

For example, pharmaceutically acceptable salts of compounds contemplatedherein as being useful may be synthesized by conventional chemicalmethods using a parent compound containing a base or an acidfunctionality. Generally, such salts may be prepared, for example, bymaking free acid or base forms of the compounds and reacting with astoichiometric quantity of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two. Generally, non-aqueousmedia such as one or more of solvents such as ether, ethyl acetate,ethanol, isopropanol or acetonitrile may be utilized. Examples of acidaddition salts include one or more of mineral acid addition salts suchas hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, andorganic acid addition salts such as one or more of acetate, maleate,fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate,methanesulphonate and p-toluenesulphonate. Examples of base additionsalts include one or more of inorganic salts such as sodium, potassium,calcium, ammonium, magnesium, and lithium salts, and organic base saltssuch as one or more of ethylenediamine, ethanolamine,N,N-dialkyl-ethanolamine, triethanolamine, and basic amino acid salts.

As used herein, the term “peptide” may refer to a single amino acid, adipeptide, a tripeptide, an oligopeptide, a polypeptide, or a carrierpeptide. An oligopeptide includes from 2 to 70 amino acids.

The terms “decreased”, “reduced”, “diminished”, or “lowered”, as usedherein, include at least a 10% change in pharmacological activity withgreater percentage changes being preferred for reduction in abusepotential and overdose potential. For instance, the change may also begreater than 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, 99%,or other increments greater than 10%.

The term “similar pharmacological activity”, as used herein, mayindicate that two compounds exhibit curves that have substantially thesame AUC, C_(max), T_(max), C_(min), and/or t_(1/2) parameters, within,in certain exemplary embodiments, about 30% of each other, and infurther exemplary embodiments within about 25%, 20%, 10%, 5%, 2%, 1%, orother increments less than 30%.

For ease of reference, the present invention will be described in termsof administration to human subjects. It will be understood, however,that such descriptions are not limited to administration to humans, butwill also include administration to other animals unless explicitlystated otherwise.

In one aspect, the present invention provides abuse-resistant opioidcompounds comprising an opioid covalently bound to at least one chemicalmoiety. The opioid compounds can also be characterized as conjugates inthat they possess a covalent attachment. The opioid compounds may alsobe characterized as conditionally bioreversible derivatives (“CBDs”) inthat, according to certain embodiments, the opioid compound remainsinactive until oral administration releases the opioid from the at leastone chemical moiety.

In accordance with certain embodiments of the present invention, theopioid compound may be represented by Formula I:

O—X_(n)—Z_(m)  (I)

wherein O is an opioid; each X is an independent chemical moiety; each Zis an independent chemical moiety that acts as an adjuvant and is adifferent chemical moiety from at least one X; n is from 1 to 50; and mis from 0 to 50. In further embodiments, n may be from 1 to 10, and mmay be from 0 to 10.

In some embodiments, m may be 0. In such embodiments, the opioidcompound may be represented by Formula II:

O—X_(n)  (II)

wherein O is an opioid; each X is an independent chemical moiety; and nis from 1 to 50. Formula II can also be written to designate thechemical moiety that is physically attached to the opioid:

O—X₁—(X)_(n-1)  (III)

wherein O is an opioid; X₁ is a chemical moiety; each X is anindependent chemical moiety that is the same or different from X₁; and nis from 1 to 50. In further embodiments, n may be from 1 to 10.

In accordance with certain embodiments of the present invention, theopioid O may be any of the natural or synthetic derivatives of Papaversomniferum such as oxymorphone or oxycodone, or any derivative, analog,or salt thereof. In some embodiments, the opioid O may be selected fromthe group consisting of a natural opioid, an ester of morphine opioid,an ether of morphine opioid, a semi-synthetic opioid, a syntheticopioid, and an endogenous opioid peptide. As such, exemplary opioidsinclude, but are not limited to, morphine; codeine; thebaine; oripavine;diacetylmorphine; 2,4-dinitrophenylmorphine;methylenedioxydimethylamphetamine; chlomaltrexamine; dihydromorphine;hydromorphinol; nicomorphine; dipropanoylmorphine; desomorphine;acetylproprionylmorphine; methyldesorphine; N-phenethylnormorphine;14-hydroxydihydrocodeine (RAM-318);7,8-dihydro-14hydroxy-N-phenethylnormorphine (RAM-378);dibenzoylmorphine; diacetyldihydromorphine; dibenzoylmorphine;6-monoacetylcodeine (6-MAC); acetyldihydrocodeine; dihydrocodeine;nalbuphine; nicocodeine; nicodicodeine; oxymorphazone; 1-iodomorphine;morphine-6-glycuronide (M6G); 6-monoacetylmorphine (6-MAM); norcodeine;normorphine; genomorphine; dextrallorphan (DXA); cyclorphan;dihydroheterocodeine; pholcodine; myrophine; 14-cinnamoyloxycodeinone;14-ethoxymetopon; 14-methoxymetopon; 14-phenylpropoxymetopon (PPOM);7-spiroindanyloxymorphone; acetylmorphone; codeinone; conorphone;codoxime; thebacon; metopon; N-phenethyl-14-ethoxymetopon; morphinone;benzylmorphine; codeine methylbromide; ethylmorphine; heterocodeine;hydromorphone; hydrocodone; oxycodone; oxymorphone; pentamorphone;semorphone; chloromorphide; ethylmorphine; buprenorphine; fentanyl;alphamethylfentanyl; alfentanil; sufentanil; remifentanil; carfentanyl;ohmefentanyl; pethidine; ketobemidone; desmethylprodine (MPPP);allylprodine; prodine; 1-methyl-4-phenyl-4-propionoxypiperidine (PEPAP);propoxyphene; dextropropoxyphene; dextromoramide; bezitramide;piritramide; levorphanol; methadone; dipipanone; levomethadyl acetate(LAAM); difenoxin; diphenoxylate; loperamide; dezocine; pentazocine;phenazocine; dihydroetorphine; etorphine; butorphanol; nalbuphine;levomethorphan; levophenacylmorphan; norlevorphanol; oxilorphan;phenomorphan; furethylnorlevorphanol; xorphanol; butorphanol; cyprodime;drotebanol; 7-PET; acetorphine; BU-48; cyprenorphine; norbuprenorphine;lefetamine; meptazinol; mitragynine; tilidine; tramadol; tapentadol;dextropropoxyphene; endorphins; enkephalins; dynorphins; andendomorphins. In some embodiments, the opioid is oxymorphone. In furtherembodiments, the opioid is oxycodone.

The opioid can have any stereogenic configuration, including bothdextro- and levo-isomers.

According to certain embodiments of the present invention, the opioidmay be an opioid salt. Pharmaceutically acceptable salts, e.g.,non-toxic, inorganic and organic acid addition salts, are known in theart. Exemplary salts include, but are not limited to,2-hydroxyethanesulfonate, 2-naphthalenesulfonate,3-hydroxy-2-naphthoate, 3-phenylpropionate, acetate, adipate, alginate,amsonate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate,bisulfate, bitartrate, borate, butyrate, calcium edetate, camphorate,camphorsulfonate, camsylate, carbonate, citrate, clavulariate,cyclopentanepropionate, digluconate, dodecylsulfate, edetate, edisylate,estolate, esylate, ethanesulfonate, finnarate, gluceptate,glucoheptanoate, gluconate, glutamate, glycerophosphate,glycollylarsanilate, hemisulfate, heptanoate, hexafluorophosphate,hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,hydroiodide, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, laurylsulphonate, malate, maleate, mandelate,mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate,mucate, naphthylate, napsylate, nicotinate, nitrate, N-methylglucamineammonium salt, oleate, oxalate, palmitate, pamoate, pantothenate,pectinate, persulfate, phosphate, phosphateldiphosphate, picrate,pivalate, polygalacturonate, propionate, p-toluenesulfonate, saccharate,salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate,suramate, tannate, tartrate, teoclate, thiocyanate, tosylate,triethiodide, undecanoate, and valerate salts, and the like.

According to certain embodiments of the present invention, the opioid isbound to one or more chemical moieties, denominated X. A chemical moietycan be any moiety that decreases the pharmacological activity of theopioid while bound to the chemical moiety as compared to unbound (free)opioid. The attached chemical moiety can be either naturally occurringor synthetic. The chemical moiety is safe for human consumption. Safefor human consumption, as used herein, may generally refer to the Foodand Drug Administration (FDA) designation of a consumable as generallyrecognized as safe (“GRAS”). In this regard, the chemical moiety isregarded as safe under the conditions of its intended use by expertsand, as such, is exempted from Federal Food, Drug, and Cosmetic Act(FFDCA) food additive tolerance requirements.

Exemplary chemical moieties may include, but are not limited to,peptides, including single amino acids, dipeptides, tripeptides,oligopeptides, and polypeptides; carboxylic acids, including α-hydroxyacids and dicarboxylic acids; and fatty acids. In some embodiments, Xmay be a carboxylic acid. In such embodiments, X may comprise lacticacid, mandelic acid, malic acid, tartaric acid, succinic acid, citricacid, or sorbic acid. In other embodiments, X may be a peptide. In suchembodiments, X may comprise an amino acid including, but not limited to,alanine (Ala or A), arginine (Arg or R), asparagine (Asn or N), asparticacid (Asp or D), cysteine (Cys or C), glycine (Gly or G), glutamic acid(Glu or E), glutamine (Gln or Q), histidine (His or H), isoleucine (lieor I), leucine (Leu or L), lysine (Lys or K), methionine (Met or M),proline (Pro or P), phenylalanine (Phe or F), serine (Ser or S),tryptophan (Trp or W), threonine (Thr or T), tyrosine (Tyr or Y), andvaline (Val or V), or a dipeptide including, but not limited to,carnosine. Each amino acid can be any one of the L- or D-enantiomers. Infurther embodiments, X may comprise at least one of alanine, proline, orcarnosine. In other embodiments, X may be a fatty acid. In suchembodiments, X may comprise oleic acid or stearic acid.

According to certain embodiments, the opioid may be bound to anotherchemical moiety Z. In such embodiments, Z may be an adjuvant analgesic.Exemplary embodiments of Z are listed below in Table 1.

In accordance with certain embodiments of the present invention, theabuse-resistant opioid compound may be represented by Formula IV:

-   -   wherein R¹ is selected from the group consisting of hydroxy,        alkoxy, and —OC(O)-alkoxy; R² is selected from the group        consisting of hydroxy and —OC(O)R⁴; R³ and R⁴ are selected from        the group consisting of —CHR⁵R⁶, —C_(a)H_(b), —C₂H₃R⁷R⁸,        —C₂H₄NHC(O)C₂H₃R⁹R¹⁰, —C₂H₄NC(O)C₂H₃R¹¹R¹², —C₂H₄NC(O)CHR²³R²⁴,        —C₂H₃CHR²⁹R³⁰, —C₂H₄NHC(O)(CH)₂C(O)OH, —C₂H₄C(O)OCHR³¹R³²,        —C₂H₄NHC(O)CHR³³R³⁴, and —C₃H₅R³⁵R³⁶; R⁵ is selected from the        group consisting of hydroxy, —OC(O)-alkoxy, —NHC(O)CHR¹⁷R¹⁸,        —NHC(O)C₂H₃R¹⁹R²⁰, —OC(O)CHR²¹R²², 4-methylimidazole,        —OC(O)C₂H₄NH₂, —OC(O)C₂H₄NHC(O)CHR²⁵R²⁶, —OC(O)C₂H₃R²⁷R²⁸,        —OC(O)(CH₂)₁₆CH₃, —OC(O)C₂H₄C(O)OH, —OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃,        —CH₂COOH, —OC(O)CH₃, —CHR³⁷R³⁸, —CH₂C(O)OCHR³⁹R⁴⁰,        —OC(O)C₃H₅R⁴¹R⁴², —CH₂C(O)OC₂H₅, —OC(O)C₂H₄NHC(O)C₄H₇NH,        —OC(O)C₄H₇NH, —OC(O)C₂H₃NHC(O)C₂H₃R⁴³R⁴⁴, —OC(O)C₂H₄CHR⁴⁵R⁴⁶,        and —OC(O)C₂H₄NHC(O)C₃H₅R⁴⁷R⁴⁸; R⁶ is selected from the group        consisting of alkyl, hydroxy, aryl, —CH₂COOH, —NHC(O)C₂H₄NH₂,        —C(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, —C(O)(CH₂)₁₆CH₃, —CH₂C(O)CHR⁴⁹R⁵⁰,        —CH₂C(O)OC₄H₉, —OC(O)CH₃, —OC(O)C₂H₄C(O)OH,        —NHC(O)C₂H₄NHC(O)CHR⁵¹R⁵², and —OC(O)(CH₂)₁₆CH₃; R⁷ is selected        from the group consisting of hydroxy, amino, —OC(O)CH₃,        —NHC(O)CHR⁵³R⁵⁴, —OC(O)CHR⁵⁵R⁵⁶, and —OC(O)C₂H₃R⁵⁷R⁵⁸; R⁸ is        selected from the group consisting of carboxyl, hydroxy,        —C(O)OC₄H₉, —OC(O)CH₃, and —C(O)OCHR⁵⁹R⁶⁰; R⁹ is selected from        the group consisting of hydroxy, carboxyl, —NHC(O)CHR⁶¹R⁶², and        —C(O)OCHR⁶³R⁶⁴; R¹⁰, R¹², R²⁹, R³¹, R³⁵, R³⁹, R⁴², R⁴⁴, R⁴⁶,        R⁴⁸, R⁵⁷, R⁵⁹, R⁶³, R⁶⁹, R⁷³, R⁷⁵ are each independently        carboxyl; R¹¹, R⁴³, R⁵², R⁵³, R⁵⁶, R⁵⁸, R⁷⁰, R⁷⁷, R⁷⁹, R⁸⁴ are        each independently hydroxy; R¹⁷, R²⁴, R³⁴ are each independently        selected from the group consisting of hydroxy, aryl, and alkyl;        R¹⁸ is selected from the group consisting of —CH₂COOH and        hydroxy; R¹⁹ and R²⁰ are each independently selected from the        group consisting of hydroxy and carboxyl; R²¹ is selected from        the group consisting of alkyl, aryl, substituted aryl, hydroxy,        amino, —OC(O)CH₃, —NHC(O)CHR⁶⁷R⁶⁸, —NHC(O)C₂H₃CHR⁶⁹R⁷⁰, and        —NHC(O)C₄H₇NH; R²² is selected from the group consisting of        alkyl, hydroxy, amino, —NHC(O)CHR⁷¹R⁷², —CH₂COOH,        —OC(O)(CH₂)₁₆CH₃, —OC(O)CH₃, —CH₂COOH, —(CH₂)₂COOH,        —CH₂C(O)OC₄H₉, —CHR⁷³R⁷⁴, —NHC(O)C₄H₇NH,        —OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, and —CHR⁷⁵R⁷⁶; R²³ is selected from        the group consisting of hydroxy, aryl, —CH₂COOH, and        —OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃; R²⁵ is selected from the group        consisting of alkyl, —C₂H₄C(O)OH, substituted aryl, and amino;        R²⁶ is selected from the group consisting of alkyl, hydroxy,        amino, substituted aryl, —NHC(O)CH₃, and —(CH₂)₂COOH; R²⁷ is        selected from the group consisting of carboxyl, —NHC(O)CHR⁷⁷R⁷⁸,        and —C(O)OC₄H₉; R²⁸ is selected from the group consisting of        amino, hydroxy, carboxyl, and —OC(O)CH₃; R³⁰ is —NHC(O)CHR⁷⁹R⁸⁰;        R³² is selected from the group consisting of aryl, —CH₂COOH, and        alkyl; R³³ is selected from the group consisting of —CH₂COOH and        hydroxy; R³ is NHC(O)CHR⁸³R⁸⁴; R³⁷, R⁶¹, R⁷⁴ are each        independently selected from the group consisting of hydroxy and        —OC(O)CH₃; R³⁸ is selected from the group consisting of carboxyl        and —C(O)OCHR⁸¹R⁸²; R⁴¹, R⁴⁵, and R⁴⁷ are each independently        amino; R⁴⁰, R⁶², R⁶⁴ are each independently selected from the        group consisting of alkyl and aryl; R⁴⁹ and R⁷⁶ are each        independently —OC(O)CH₃; R⁵⁰, R⁵¹, R⁵⁴, R⁵⁵, R⁶⁰, R⁷⁸, R⁸⁰, R⁸³        are each independently alkyl; R⁶⁷ is selected from the group        consisting of alkyl and —NHC(O)CH₃; R⁶⁸ is selected from the        group consisting of hydroxy and —(CH₂)₄NH₂; R⁷¹ is selected from        the group consisting of hydroxy, —NHC(O)CH₃, and amino; R⁷² is        selected from the group consisting of alkyl and —C₄H₈NH₂; R⁸¹ is        selected from the group consisting of carboxyl, aryl, and        —CH₂COOH; R⁸² is selected from the group consisting of alkyl,        aryl, carboxyl, and —CH₂COOH; T is a pharmaceutically acceptable        salt; a is from 1 to 30; b is from 1 to 50; c is from 0 to 5;        and d is from 1 to 10.

According to certain embodiments, the abuse-resistant opioid compoundmay be selected from one or more of:

Ex, Mass No. Structure Spec ¹H NMR Data A1

580 ¹H NMR (300 MHz, CDCl₃) δ 9.99 (s, 1H), 6.78 (d, J = 8.4 Hz, 1H),6.70 (d, J = 8.1 Hz, 1H), 5.57 (apparent d, J = 4.5 Hz, 1H), 5.40-5.30(m, 2H), 5.05 (s, 1H), 4.35 (br s, 1H), 3.86 (s, 3H), 3.48 (d, J = 10.2Hz, 1H), 3.27-3.20 (m, 2H), 3.10-2.84 (m, 5H), 2.72- 2.66 (m, 1H), 2.43(t, J = 7.2 Hz, 2H), 2.12 (d, J = 17.7 Hz, 1H), 2.02-2.01 (m, 4H),1.74-1.61 (m, 4H), 1.32- 1.27 (m, 20H), 0.88 (t, J = 6.6 Hz, 3H) A2

450 ¹H NMR (300 MHz, DMSO-d₆) δ 9.14 (br s, 1H), 7.46-7.40 (m, 2H),7.39- 7.31 (m, 3H), 6.83 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.1 Hz, 1H),6.28- 6.24 (m, 2H), 5.48-5.45 (m, 1H), 5.27 (d, J = 5.7 Hz, 1H), 4.92(s, 1H), 3.68 (s, 3H), 3.64-3.62 (m, 1H), 3.44-3.38 (m, 1H), 3.13-3.05(m, 2H), 2.82 (br s, 3H), 2.27-2.19 (m, 1H), 2.09-2.03 (m, 1H), 1.61 (d,J = 12.6 Hz, 1H) A3

432 ¹H NMR (300 MHz, DMSO-d₆) δ 12.7 (br s, 1H), 9.18 (br s, 1H), 6.82(d, J = 8.1 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.29 (s, 1H), 5.62 (br s,1H), 5.52 (d, J = 4.5 Hz, 1H), 4.98 (s, 1H), 4.33 (br s, 1H), 3.76 (s,3H), 3.57 (s, 3H), 3.15-3.06 (m, 2H), 2.89-2.84 (m, 4H), 2.73-2.63 (m,1H), 2.29 (dd, J = 6.3, 18.0 Hz, 1H), 2.33-2.25 (m, 1H), 1.63 (d, J =11.4 Hz, 1H) A4a

582 ¹H NMR (300 MHz, CDCl₃) δ 6.71 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 8.1Hz, 1H), 5.57 (dd, J = 4.8, 3.9 Hz, 1H), 5.01 (s, 1H), 4.72 (br s, 1H),3.84 (s, 3H) 3.17 (d J = 18.6 Hz, 1H), 2.85 (d, J = 6.3 Hz, 1H), 2.62(dd, J = 18.9, 6.6 Hz, 1H), 2.47-2.18 (m, 8H), 2.16-2.15 (m, 2H),1.70-1.59 (m, 3H), 1.30-1.25 (m, 28H), 0.88 (t, J = 6.3 Hz, 3H) A4b

554 ¹H NMR (300 MHz, CDCl₃) δ 6.71 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 8.4Hz, 1H), 5.57 (dd, J = 4.5, 3.6 Hz, 1H), 5.01 (s, 1H), 3.84 (s, 3H),3.17 (d, J = 18.6 Hz 1H) 2.85 (d, J = 6.3 Hz, 1H), 2.62 (dd, J = 18.6,6.3 Hz, 1H), 2.47-2.35 (m, 6H), 2.32-2.22 (m, 2H), 2.16-2.15 (m, 2H),1.68-1.59 (m, 3H), 1.30-1.25 (m, 24H), 0.88 (t, J = 6.3 Hz, 3H) A5

388 ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (s, 1H), 6.86 (d, J = 8.1 Hz, 1H),6.75 (d, J = 8.4 Hz, 1H), 6.30 (s, 1H), 5.60 (d, J = 6.0 Hz, 1H), 5.54(dd, J = 6.0, 2.1 Hz, 1H), 5.00 (s, 1H), 4.33-4.24 (m, 1H), 3.75 (s,3H), 3.64 (d, J = 6.6 Hz, 1H), 3.43 (d, J = 19.8 Hz, 1H), 3.11 (dd, J =18.9, 6.6 Hz, 2H), 2.84 (d, J = 3.9 Hz, 3H), 2.69-2.57 (m, 1H),2.49-2.41 (m, 1H), 2.32-2.24 (m, 1H), 2.07 (d, J = 17.7 Hz, 1H), 1.64(d, J = 11.7 Hz, 1H), 1.35 (d, J = 6.9 Hz, 3H) A6

459 ¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (br s, 1H), 8.48 (s, 3H), 6.87 (d,J = 8.4 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.36 (s, 1H), 5.61 (dd, J =6.0, 1.8 Hz, 1H), 5.35 (q, J = 6.9 Hz, 1H), 5.01 (s, 1H), 4.24-4.22 (m,1H), 3.76 (s, 3H), 3.69 (d, J = 6.0 Hz, 1H), 3.43 (d, J = 20.1 Hz, 1H),3.12 (dd, J = 19.2, 6.9 Hz, 1H), 2.85 (s, 3H), 2.64- 2.57 (m, 1H),2.49-2.27 (m, 2H, partially obscured by solvent peak), 2.06 (apparent d,J = 18.0 Hz, 1H), 1.63 (d, J = 11.1 Hz, 1H), 1.56 (d, J = 6.9 Hz, 3H),1.48 (d, J = 7.2 Hz, 3H) A7

460 ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (br s, 1H), 6.86 (d, J = 8.1 Hz,1H), 6.75 (d, J = 8.4 Hz, 1H), 6.30 (s, 1H), 5.59 (dd, J = 5.7, 1.8 Hz,1H), 5.50 (br s, 1H), 5.17 (q, J = 6.9 Hz, 1H), 5.00 (s, 1H), 4.25-4.22(m, 1H), 3.75 (s, 3H), 3.65 (d, J = 6.0 Hz, 1H), 3.46-3.38 (m, 1H,partially obscured by water peak), 3.16-3.07 (m, 2H), 2.84 (apparent d,J = 5.1 Hz, 3H), 2.69-2.57 (m, 1H), 2.49-2.26 (m, 2H, partially obscuredby solvent peak), 2.07 (apparent d, J = 18.0 Hz, 1H), 1.65 (d, J = 11.4Hz, 1H), 1.51 (d, J = 11.4 Hz, 3H), 1.31 (d, J = 6.6 Hz, 3H) A8

410 ¹H NMR (300 MHz, CDCl₃) δ 7.35- 7.26 (m, 1H), 6.71 (d, J = 8.4 Hz,1H), 6.62 (d, J = 8.1 Hz, 1H), 6.26- 6.10 (m, 2H), 5.85 (d, J = 15.3 Hz,1H), 5.64 (overlapping dd, J = 3.9 Hz, 1H), 5.06 (s, 1H), 4.72 (br s,1H), 3.84 (s, 3H), 3.18 (d, J = 18.6 Hz, 1H), 2.86 (d, J = 6.3 Hz, 1H),2.63 (dd, J = 18.6, 6.3 Hz, 1H), 2.47-2.42 (m, 1H), 2.38 (s, 3H),2.33-2.19 (m, 2H), 2.18-2.16 (m, 2H), 1.87 (d, J = 5.4 Hz, 3H), 1.63(dd, J = 13.5, 3.0 Hz, 1H) A9

432 ¹H NMR (300 MHz, DMSO-d₆) δ 12.43 (br s, 1H), 9.18 (br s, 1H), 6.86(d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.29 (br s, 1H), 5.90 (brs, 1H), 5.55-5.54 (m, 1H), 4.97 (s, 1H), 4.47 (br s, 1H), 3.75 (s, 3H),3.62 (s, 1H), 3.45-3.37 (m, 1H), 3.12-3.06 (m, 2H), 2.83 (s, H),2.74-2.53 (m, 3H), 2.33-2.22 (m, 1H), 2.07 (d, J = 18.3 Hz, 1H), 1.63(d, J = 12.3 Hz, 1H), one proton obscured by solvent peaks A10

450 ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (br s, 1H), 7.49-7.33 (m, 5H), 6.84(d, J = 8.1 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.28-6.24 (m, 2H), 5.44-5.41 (m, 1H), 5.28 (d, J = 5.1 Hz, 1H), 4.95 (s, 1H), 3.68 (s, 3H),3.64- 3.62 (m, 1H), 3.44-3.35 (m, 1H), 3.13-3.04 (m, 2H), 2.83 (s, 3H),2.69-2.54 (m, 1H), 2.44-2.43 (m, 1H), 2.34 (dd, J = 18.0, 5.4 Hz, 1H),2.04 (d, J = 18.0 Hz, 1H) A11

522 ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (br s, 1H), 7.57-7.55 (m, 2H),7.48- 7.45 (m, 3H), 6.81 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H),6.31 (br s, 1H), 6.15 (s, 1H), 5.57-5.53 (m, 2H), 4.94 (s, 1H),4.34-4.26 (m, 1H), 3.64 (br s, 4H), 3.44-3.37 (m, 1H, partially obscuredby water peak), 3.13-3.05 (m, 2H), 2.82 (s, 3H), 2.62-2.57 (m, 1H),2.49-2.39 (m, 1H, partially obscured by solvent peak), 2.30-2.22 (m,1H), 2.08-2.02 (m, 1H), 1.62 (d, J = 12.0 Hz, 1H), 1.37 (d, J = 6.6 Hz,3H) A12

459 ¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (br s, 1H), 8.09 (d, J = 6.9 Hz,1H), 6.86 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.28 (s, 1H),5.53-6.50 (m, 1H), 5.00 (s, 1H), 4.39-4.34 (m, 1H), 4.03-3.99 (m, 1H),3.75 (s, 3H), 3.64 (d, J = 5.7 Hz, 1H), 3.50-3.35 (m, 2H), 3.13-3.06 (m,2H), 2.84 (d, J = 4.5 Hz, 3H), 2.75-2.55 (m, 1H), 2.32-2.24 (m, 1H),2.06 (d, J = 18.0 Hz, 1H), 1.59 (d, J = 11.7 Hz, 1H), 1.40 (d, J = 7.2Hz, 3H), 1.22 (d, J = 10.5 Hz, 3H) A13

485 ¹H NMR (300 MHz, DMSO-d₆) δ 9.93 (br s, 1H), 9.22 (br s, 1H), 9.02(br s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.35 (s,1H), 5.62 (dd, J = 5.7, 1.8 Hz, 1H), 5.35 (q, J = 7.2 Hz, 1H), 4.99 (s,1H), 4.54 (br s, 1H), 3.75 (s, 3H), 3.69 (d, J = 5.7 Hz, 1H), 3.42-3.37(m, 1H, partially obscured by water peak), 3.25 (br s, 2H), 3.16-3.07(m, 2H), 2.85 (apparent d, J = 4.8 Hz, 3H), 2.65- 2.57 (m, 1H),2.49-2.27 (m, 3H, partially obscured by solvent peak), 2.18-1.88 (m,4H), 1.63 (d, J = 12.0 Hz, 1H), 1.57 (d, J = 7.2 Hz, 3H) A14

¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (br s, 1H), 9.01 (s, 1H), 8.85 (d, J =7.2 Hz, 1H), 7.77 (br s, 3H), 7.49 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H),6.77 (d, J = 8.4 Hz, 1H), 6.35 (br s, 1H), 5.53- 5.51 (m, 1H), 4.94 (s,1H), 4.69 (q, J = 8.1 Hz, 1H), 3.75 (s, 3H), 3.67 (d, J = 6.3 Hz, 1H),3.44 (d, J = 20.1 Hz, 1H), 3.23-3.09 (m, 4H), 3.00-2.92 (m, 2H), 2.85(s, 3H), 2.70-2.55 (m, 1H), 2.30 (dd, J = 18.6, 6.6 Hz, 1H), 2.04 (d, J= 17.7 Hz, 1H), 1.62 (, J = 11.4 Hz, 1H), two protons not observed A15

459 ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (br s, 1H), 8.02 (br s, 3H), 6.86(d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.38 (s, 1H), 5.59 (dd, J= 6.0, 1.8 Hz, 1H), 5.17 (q, J = 7.2 Hz, 1H), 4.99 (s, 1H), 3.76 (s,3H), 3.70 (d, J = 6.0 Hz, 1H), 3.43 (d, J = 20.1 Hz, 1H), 3.16-3.04 (m,4H), 2.85-2.79 (m, 5H), 2.65-2.57 (m, 1H), 2.49- 2.27 (m, 2H, partiallyobscured by solvent peak), 2.05 (apparent d, J = 18.0 Hz, 1H), 1.63 (d,J = 10.8 Hz, 1H), 1.52 (d, J = 7.2 Hz, 3H) A16

521 ¹H NMR (300 MHz, DMSO-d₆, Mixture of diastereomers) δ 9.22 (br s,1H), 8.03 (br s, 3H), 7.57-7.56 (m, 2H), 7.49-7.46 (m, 3H), 6.86-6.80(m, 1H), 6.76-6.72 (m, 1H), 6.38 (s, 1H), 6.14 (s, 0.66H), 6.13 (s,0.34H), 5.55 (dd, J = 6.3, 2.1 Hz, 0.66H), 5.47 (dd, J = 6.0. 1.8 Hz,0.34H), 4.96 (s, 0.66H), 4.93 (s, 0.34H), 3.72 (s, 1.02H), 3.70-3.68 (m,1H), 3.64 (s, 1.98H), 3.41 (d, J = 20.1 Hz, 1H), 3.14-3.07 (m, 4H),2.89-2.83 (m, 5H), 2.63-2.59 (m, 1H), 2.49-2.27 (m, 2H, partiallyobscured by solvent peak), 2.04 (apparent d, J = 18.3 Hz, 1H), 1.61 (d,J = 11.7 Hz, 1H) A17

521 ¹H NMR (300 MHz, DMSO-d₆) δ 8.13 (t, J = 6.0 Hz, 1H), 7.42-7.24 (m,7H), 6.83 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 6.20 (d, J =4.8 Hz, 1H), 5.47-5.45 (m, 1H), 4.93 (s, 1H), 4.89 (d, J = 4.8 Hz, 1H),3.74 (s, 3H), 3.41-3.28 (m, 2H), 3.10-2.80 (m, 2H), 2.78-2.60 (m, 5H),2.46-2.33 (m, 2H), 2.30-2.12 (m, 1H), 2.02 (d, J = 18.0 Hz, 1H),1.60-1.50 (m, 1H), one proton not observed A18

459 ¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (br s, 1H), 8.09 (d, J = 6.9 Hz,1H), 6.86 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.28 (s, 1H),5.53-5.50 (m, 1H), 5.00 (s, 1H), 4.39-4.34 (m, 1H), 4.03-3.99 (m, 1H),3.75 (s, 3H), 3.64 (d, J = 5.7 Hz, 1H), 3.50-3.35 (m, 2H), 3.13-3.06 (m,2H), 2.84 (d, J = 4.5 Hz, 3H), 2.75-2.55 (m, 1H), 2.32-2.24 (m, 1H),2.06 (d, J = 18.0 Hz, 1H), 1.59 (d, J = 11.7 Hz, 1H), 1.40 (d, J = 7.2Hz, 3H), 1.22 (d, J = 10.5 Hz, 3H) A19

566 ¹H NMR (300 MHz, DMSO-d₆, Mixture of diastereomers) δ 7.56- 7.54 (m,2H), 7.46-7.44 (m, 3H), 6.75-6.62 (m, 1H), 6.09 (s, 0.68H), 6.05 (s,0.32H), 5.54 (dd, J = 5.4, 2.4 Hz, 0.68H), 5.42 (dd, J = 5.4, 2.4 Hz,0.32H), 4.81 (s, 1H), 4.29-4.25 (m, 1H), 3.70 (s, 0.96H), 3.61 (s,2.04H), 3.13 (d, J = 18.9 Hz, 1H), 2.93-2.83 (m, 2H), 2.73-2.59 (m, 2H),2.49- 2.40 (m, 1H, partially obscured by solvent peak), 2.38 (s, 3H),2.31- 1.95 (m, 5H), 1.39 (d, J = 10.8 Hz, 1H), CO₂H, HCl, and two OHprotons not observed A20

517 ¹H NMR (300 MHz, DMSO-d₆) δ 9.09 (br s, 1H), 8.52 (br s, 2H), 6.86(d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.31 (br s, 1H),5.63-5.60 (m, 1H), 5.35 (q, J = 6.9 Hz, 1H), 5.02 (s, 1H), 4.20(apparent t, J = 6.6 Hz, 1H), 3.75 (s, 3H), 3.65 (br s, 1H), 3.43 (d, J= 19.8 Hz, 1H, partially obscured by water peak), 3.14-3.05 (m, 2H),2.83 (s, 3H), 2.62-2.56 (m, 1H), 2.49-2.27 (m, 3H, partially obscured bysolvent peak), 2.10-2.04 (m, 3H), 1.65-1.58 (m, 1H), 1.57 (d, J = 7.2Hz, 3H), CO₂H proton not observed, one proton obscured by solvent peaksA21

503 ¹H NMR (300 MHz, DMSO-d₆) δ 12.5 (br s, 1H), 9.21 (br s, 1H), 8.45(d, J = 6.3 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H),6.34 (s, 1H), 5.54-5.52 (m, 1H), 4.99 (s, 1H), 4.37-4.31 (m, 2H), 3.75(s, 3H), 3.69-3.65 (m, 2H), 3.39 (s, 3H), 3.13-3.07 (m, 2H), 2.84 (d, J= 4.5 Hz, 3H), 2.28 (d, J = 6.3 Hz, 1H), 2.05 (d, J = 17.7 Hz, 1H), 1.63(d, J = 11.1 Hz, 1H), 1.36 (d, J = 7.5 Hz, 3H), 1.25 (d, J = 7.5 Hz, 1H)A22

521 ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (br s, 1H), 8.13 (t, J = 6.3 Hz,1H), 7.34-7.31 (m, 2H), 7.29-7.23 (m, 3H), 6.86 (d, J = 8.4 Hz, 1H),6.75 (d, J = 8.1 Hz, 1H), 6.26 (s, 1H), 6.21 (d, J = 4.5 Hz, 1H),5.50-5.48 (m, 1H), 4.97 (s, 1H), 4.89 (d, J = 4.2 Hz, 1H), 3.75 (m, 3H),3.64-3.63 (m, 1H), 3.46-3.33 (m, 3H), 3.15-3.06 (m, 2H), 2.84 (d, J =4.5 Hz, 3H), 2.63 (t, J = 6.9 Hz, 3H), 2.28-2.22 (m, 1H), 2.05 (d, J =17.7 H, 1H), 1.63 (d, J = 12.9 Hz, 1H) A23

503 ¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (t, J = 5.4 H, 1H), 6.75 (d, J =8.1 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 5.55- 5.52 (m, 1H), 4.87 (s, 1H),4.24-4.20 (m, 1H), 3.73 (s, 3H), 3.14 (d, J = 18.9 Hz, 2H), 2.91 (d, J =6.0 Hz, 1H), 2.73-2.55 (m, 3H), 2.48-2.42 (m, 2H), 2.39-2.20 (m, 5H),2.17- 1.90 (m, 3H), 1.40 (d, J = 11.1 Hz, 1H), CO₂H and two OH protonsnot observed, one proton obscured by solvent peaks A24

521 ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (br s, 1H), 8.43 (d, J = 6.9 Hz,1H), 7.43-7.40 (m, 2H), 7.34-7.21 (m, 3H), 6.85 (d, J = 8.1 Hz, 1H),6.76 (d, J = 8.4 Hz, 1H), 6.27-6.22 (m, 2H), 5.41-5.40 (m, 1H), 4.96 (d,J = 4.8 Hz, 2H), 4.40-4.35 (m, 1H), 3.75 (s, 3H), 3.70-3.55 (m, 1H),3.50-3.35 (m, 1H), 3.20-3.00 (m, 2H), 2.83 (s, 3H), 2.27-2.22 (m, 1H),2.05-1.99 (m, 1H), 1.65-1.61 (m, 1H), 1.40 (d, J = 7.2 Hz, 3H), oneproton obscured by solvent peaks A25

593 ¹H NMR (300 MHz, DMSO-d₆, Mixture of diastereomers) δ 9.17 (br s,1H), 7.82-7.79 (m, 1H), 7.57-7.54 (m, 2H), 7.47-7.45 (m, 3H), 6.86- 6.80(m, 1H), 6.74-6.71 (m, 1H), 6.30 (s, 1H), 6.09 (s, 0.64H), 6.07 (s,0.36H), 5.56-5.46 (m, 2H), 4.96 (s, 0.64H), 4.93 (s, 0.36H), 3.98-3.90(m, 1H), 3.71 (s, 1.08H), 3.63 (s, 1.92H), 3.62 (br s, 1H), 3.46-3.32(m, 3H, partially obscured by water peak), 3.14-3.05 (m, 2H), 2.83 (s,3H), 2.65-2.61 (m, 2H), 2.49-2.39 (m, 2H, partially obscured by solventpeak), 2.30-2.24 (m, 1H), 2.09-2.03 (m, 1H), 1.65-1.61 (m, 1H), 1.19-1.16 (m, 3H) A26

596 ¹H NMR (300 MHz, DMSO-d₆) δ 9.19 (br s, 1H), 8.94 (s, 1H), 8.59 (d,J = 7.5 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.45 (s, 1H), 6.87 (d, J =8.4 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.29 (s, 1H), 5.53-5.51 (m, 2H),4.96 (s, 1H), 4.68-4.65 (m, 1H), 3.98-3.88 (m, 1H), 3.75 (s, 3H),3.60-3.70 (m, 1H), 3.25-3.23 (m, 3H), 3.15-3.10 (m, 4H), 2.85 (s, 3H),2.33-2.28 (m, 3H), 2.07-2.02 (m, 1H), 1.63 (d, J = 11.1 Hz, 1H),1.228-1.24 (m, 2H), 1.17 (d, J = 6.9 Hz, 3H) A27

589 ¹H NMR (300 MHz, DMSO-d₆) δ 12.19 (br s, 1H), 9.17 (br s, 1H), 7.99(d, J = 7.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H),6.30 (s, 1H), 5.60 (dd, J = 6.0, 2.1 Hz, 1H), 5.54 (br s, 1H), 5.16 (q,J = 6.9 Hz, 1H), 5.01 (s, 1H), 4.42-4.34 (m, 1H), 4.01 (q, J = 6.9 Hz,1H), 3.75 (s, 3H), 3.65 (d, J = 6.3 Hz, 1H), 3.43 (d, J = 20.1 Hz, 1H,partially obscured by water peak), 3.16-3.07 (m, 2H), 2.84 (apparent d,J = 4.8 Hz, 3H), 2.66-2.57 (m, 1H), 2.49-2.43 (m, 1H, partially obscuredby solvent peak), 2.37-2.23 (m, 3H), 2.15-2.05 (m, 2H), 1.97-1.85 (m,1H), 1.64 (d, J = 10.8 Hz, 1H), 1.52 (d, J = 6.9 Hz, 3H), 1.22 (d, J =6.9 Hz, 3H) A28

602 ¹H NMR (300 MHz, DMSO-d₆) δ 9.44 (br s, 1H), 7.89 (dt, J = 12.9, 6.0Hz, 2H) 6.92 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.51-5.49(m, 2H), 5.10 (s, 1H), 4.76 (d, J = 5.4 Hz, 1H), 3.98-3.94 (m, 2H), 3.77(s, 3H), 3.40-3.20 (m, 7H), 3.04-2.96 (m, 4H), 2.65-2.61 (m, 3H), 2.09(d, J = 18.3 Hz, 1H), 1.81 (d, J = 12.0 Hz, 1H), 1.21 (d, J = 4.5 Hz,3H), 1.19 (d, J = 4.2 Hz, 6H) A29

521 ¹H NMR (300 MHz, DMSO-d₆, Mixture of diastereomers) δ 9.19 (br s,1H), 7.91 (br s, 3H), 7.57-7.55 (m, 2H), 7.48-7.46 (m, 3H), 6.87-6.81(m, 1H), 6.76-6.72 (m, 1H), 6.32 (s, 1H), 6.14 (s, 0.42H), 6.13 (s,0.58H), 5.56-5.54 (m, 0.42H), 5.48-5.46 (m, 0.58H), 4.96 (s, 0.42H),4.92 (s, 0.58H), 3.72 (s, 1.74H), 3.67 (br s, 1H), 3.75 (s, 1.26H), 3.42(d, J = 20.4 Hz, 1H), 3.14-3.07 (m, 4H), 2.86- 2.83 (m, 5H), 2.64-2.57(m, 1H), 2.49-2.33 (m, 2H, partially obscured by solvent peak),2.08-2.00 (m, 1H), 1.61 (d, J = 12.6 Hz, 1H) A30

503 ¹H NMR (300 MHz, DMSO-d₆) δ 12.96 (br s, 1H), 9.17 (br s, 1H), 8.01(d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H),6.27 (s, 1H), 5.65 (br s, 1H), 5.51 (dd, J = 6.0, 2.1 Hz, 1H), 4.97 (s,1H), 4.66 (q, J = 8.1 Hz, 1H), 4.01 (q, J = 6.6 Hz, 1H), 3.75 (s, 3H),3.64 (d, J = 6.0 Hz, 1H), 3.15-3.01 (m, 3H), 2.96 (d, J = 6.3 Hz, 1H),2.91 (d, J = 6.3 Hz, 1H), 2.84 (d, J = 4.5 Hz, 3H), 2.75-2.55 (m, 1H),2.32-2.24 (m, 1H), 2.06 (d, J = 18.0 Hz, 1H), 1.64 (d, J = 10.2 Hz, 1H),1.21 (d, J = 6.6 Hz, 3H) A31

633 ¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (d, J = 7.2 Hz, 1H), 6.75 (d, J =8.1 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 5.57 (dd, J = 5.7, 2.4 Hz, 1H),5.14 (q, J = 7.2 Hz, 1H), 4.87 (s, 1H), 4.41-4.34 (m, 1H), 4.23 (dd, J =8.1, 4.8 Hz, 1H), 3.73 (s, 3H), 3.15 (d, J = 18.9 Hz, 1H), 2.95 (d, J =5.4 Hz, 1H), 2.73-2.63 (m, 1H), 2.49-2.24 (m, 9H, partially obscured bysolvent peak), 2.16-1.96 (m, 4H), 1.88-1.76 (m, 1H), 1.52 (d, J = 7.2Hz, 3H), two CO₂H, HCl, and two OH protons not observed, one protonobscured by solvent peaks A32

503 ¹H NMR (300 MHz, DMSO-d₆) δ 7.77 (br s, 1H), 6.84 (d, J = 8.1 Hz,1H), 6.74 (d, J = 8.4 Hz, 1H), 5.60-5.58 (m, 1H), 5.13 (q, J = 6.9 Hz,1H), 4.99 (s, 1H), 3.76 (s, 3H), 3.64-3.52 (m, 2H), 3.04-2.91 (m, 4H),2.76- 2.63 (m, 5H), 2.49-2.40 (m, 1H, partially obscured by solventpeak), 2.28-2.22 (m, 1H), 2.06 (apparent d, J = 17.4 Hz, 1H), 1.60 (d, J= 9.9 Hz, 1H), 1.51 (d, J = 6.9 Hz, 3H), CO₂H, NH₂, and OH protons notobserved A33

575 ¹H NMR (300 MHz, DMSO-d₆) δ 7.94 (d, J = 8.1 Hz, 1H), 6.77 (d, J =8.1 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 5.64 (d, J = 5.1 Hz, 1H), 5.57(dd, J = 5.7, 2.1 Hz, 1H), 5.11 (q, J = 6.9 Hz, 1H), 4.90 (s, 1H),4.62-4.55 (m, 1H), 4.00-3.94 (m, 1H), 3.74 (s, 3H), 3.20 (d, J = 19.8Hz, 1H, partially obscured by water peak), 3.08 (br s, 1H), 2.89-2.78(m, 3H), 2.63-2.57 (m, 1H), 2.49-2.31 (m, 2H, partially obscured bysolvent peak), 2.17-1.97 (m, 2H), 1.48 (d, J = 6.9 Hz, 3H), 1.47-1.45(m, 1H), 1.19 (d, J = 6.6 Hz, 3H), CO₂H and CH₃CO₂H protons notobserved, four protons obscured by solvent peaks A34

637 ¹H NMR (300 MHz, DMSO-d₆, Mixture of diastereomers) δ 8.04 (br s,1H), 7.56-7.54 (m, 2H), 7.46-7.44 (m, 3H), 6.75-6.69 (m, 1H), 6.66- 6.62(m, 1H), 6.06 (s, 1H), 5.55-5.52 (m, 0.43H), 5.43-5.41 (m, 0.57H), 4.80(s, 1H), 4.24-4.19 (m, 1H), 3.70 (s, 1.71H), 3.61 (s, 1.29H), 3.16-3.09(m, 1H, partially obscured by water peak), 2.90 (br s, 1H), 2.67-2.58(m, 2H), 2.49-2.22 (m, 8H, partially obscured by solvent peak),2.12-1.93 (m, 3H), 1.39 (d, J = 11.4 Hz, 1H), CO₂H and HCl protons notobserved, four protons obscured by solvent peaks A35

726 ¹H NMR (300 MHz, DMSO-d₆) δ 9.41 (br s, 1H), 8.24 (t, J = 5.7 Hz,1H), 8.16 (t, J = 5.7 Hz, 1H), 7.40-7.21 (m, 10H), 6.92 (d, J = 8.4 Hz,1H), 6.79 (d, J = 8.4 Hz, 1H), 6.26 (br s, 2H), 5.37-5.35 (m, 1H), 5.07(s, 1H), 4.91 (d, J = 6.0 Hz, 2H), 4.70 (d, J = 6.0 Hz, 1H), 3.77 (s,3H), 3.52 (d, J = 20.1 Hz, 1H), 3.38-3.18 (m, 6H), 2.99-2.87 (m, 4H),2.82-2.52 (m, 5H), 2.05 (d, J = 18.9 Hz, 1H), 1.78 (d, J = 13.5 Hz, 1H)A36

546 ¹H NMR (300 MHz, DMSO-d₆) δ 8.85-7.92 (br s, 6H), 6.92 (d, J = 8.1Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.54-5.52 (m, 1H), 5.07 (s, 1H), 4.67(d, J = 6.0 Hz, 1H), 4.27 (t, J = 5.7 Hz, 1H), 3.93 (t, J = 8.7 Hz, 1H),3.77 (s, 3H), 3.50 (d, J = 20.1 Hz, 1H), 3.21-2.97 (m, 5H), 2.81 (s,3H), 2.77-2.65 (m, 4H), 2.13 (d, J = 18.3 Hz, 1H), 1.77 (d, J = 11.4 Hz,1H), two CO₂H protons not observed A37

488 ¹H NMR (300 MHz, DMSO-d₆) δ 12.25 (br s, 1H), 9.19 (s, 1H), 6.86 (d,J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.31 (br s, 1H), 5.59-5.57(m, 1H), 5.11 (q, J = 6.9 Hz, 1H), 4.99 (s, 1H), 3.75 (s, 3H), 3.65 (d,J = 6.0 Hz, 2H), 3.43 (d, J = 19.8 Hz, 1H), 3.14- 3.31 (m, 2H), 2.84 (d,J = 4.5 Hz, 3H), 2.62-2.60 (m, 3H), 2.48-2.40 (m, 2H), 2.29 (dd, J =17.7, 11.7 Hz, 1H), 2.06 (d, J = 18.0 Hz, 1H), 1.65 (d, J = 11.1 Hz,1H), 1.49 (d, J = 3.9 Hz, 3H) A38

690 ¹H NMR (300 MHz, DMSO-d₆) δ 12.96 (br s, 2H), 9.35 (br s, 1H), 8.03(d, J = 8.4 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H),6.77 (d, J = 8.4 Hz, 1H), 5.68 (br s, 2H), 5.44-5.42 (m, 1H), 5.03 (s,1H), 4.69-4.62 (m, 3H), 4.03-3.97 (m, 2H), 3.76 (s, 3H), 3.28-3.13 (m,1H), 3.16-3.07 (m, 2H), 3.04-2.82 (m, 8H), 2.73-2.63 (m, 2H), 2.11 (d, J= 18.3 Hz, 1H), 1.76 (d, J = 12.9 Hz, 1H), 1.20 (d, J = 9.0 Hz, 6H) A39

504 ¹H NMR (300 MHz, DMSO-d₆) δ 12.36 (br s, 1H), 9.19 (br s, 1H), 6.86(d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 5.83 (br s,1H), 5.60-5.58 (m, 1H), 5.18 (q, J = 16.2 Hz, 1H), 5.00 (s, 1H), 4.73(dd, J = 8.7, 3.9 Hz, 1H), 3.75 (s, 3H), 3.65 (d, J = 6.3 Hz, 1H), 3.43(d, J = 20.1 Hz, 1H), 3.14-3.07 (m, 2H), 2.84 (d, J = 4.8 Hz, 3H),2.78-2.58 (m, 2H), 2.33-2.26 (m, 1H), 2.07 (d, J = 17.7 Hz, 1H), 1.65(d, J = 11.4 Hz, 1H), 1.51 (d, J = 7.2 Hz, 3H), one proton obscured bysolvent peaks A40

550 ¹H NMR (300 MHz, DMSO-d₆) δ 12.28 (br s, 1H), 9.16 (br s, 1H),7.56-7.54 (m, 2H), 7.50-7.45 (m, 3H), 6.81 (d, J = 8.4 Hz, 1H), 6.72 (d,J = 8.4 Hz, 1H), 6.31 (s, 1H), 6.10 (s, 1H), 5.55-5.53 (m, 1H), 4.95 (s,1H), 3.64 (s, 3H), 3.41 (d, J = 19.8 Hz, 1H), 3.14-3.05 (m, 2H), 2.83(d, J = 4.5 Hz, 3H), 2.69-2.66 (m, 3H), 2.56-2.49 (m, 2H), 2.45-2.40 (m,1H), 2.30-2.22 (m, 1H), 2.05 (d, J = 18.3 Hz, 1H), 1.62 (d, J = 11.4 Hz,1H) A41

522 ¹H NMR (300 MHz, DMSO-d₆) δ 9.17 (br s, 1H), 7.46-7.42 (m, 2H),7.37- 7.27 (m, 3H), 6.85 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H),6.26 (s, 1H), 6.15 (d, J = 5.4 Hz, 1H), 5.50- 5.48 (m, 1H), 5.23-5.16(m, 1H), 4.84 (s, 1H), 3.72 (s, 3H), 3.64 (br s, 1H), 3.42 (d, J = 20.1Hz, 1H), 3.15-3.06 (m, 2H), 2.84 (s, 3H), 2.64-2.57 (m, 1H), 2.49-2.40(m, 1H, partially obscured by solvent peak), 2.34-2.23 (m, 1H), 2.04(apparent d, J = 18.3 Hz, 1H), 1.62 (d, J = 8.7 Hz, 1H), 1.48 (d, J =6.9 Hz, 3H) A42

714 ¹H NMR (300 MHz, DMSO-d₆, Mixture of diastereomers) δ 9.17 (br s,1H), 7.56-7.53 (m, 2H), 7.46-7.44 (m, 3H), 6.85-6.79 (m, 1H), 6.75- 6.71(m, 1H), 6.29 (s, 1H), 6.09 (s, 0.49H), 6.07 (s, 0.51H), 5.53 (dd, J =6.0, 2.1 Hz, 0.49H), 5.45 (dd, J = 6.0, 2.1 Hz, 0.51H), 5.33-5.30 (m,2H), 4.94 (s, 0.49H), 4.90 (s, 0.51H), 3.71 (s, 1.47H), 3.64 (br s,2.53H), 3.45- 3.38 (m, 1H), 3.13-3.05 (m, 2H), 2.82 (s, 3H), 2.64-2.55(m, 1H), 2.49-2.40 (m, 3H, partially obscured by solvent peak),2.28-2.22 (m, 1H), 2.07-1.96 (m, 5H), 1.64-1.54 (m, 3H), 1.32- 1.24 (m,20H), 0.84 (t, J = 6.6 Hz, 3H) A43

716 ¹H NMR (300 MHz, DMSO-d₆, Mixture of diastereomers) δ 9.17 (br s,1H), 7.56-7.53 (m, 2H), 7.46-7.44 (m, 3H), 6.86-6.80 (m, 1H), 6.75- 6.71(m, 1H), 6.30 (br s, 1H), 6.09 (s, 0.51H), 6.07 (s, 0.49H), 5.53 (dd, J= 6.0, 2.1 Hz, 0.1H), 5.45 (dd, J = 6.0, 2.1 Hz, 0.49H), 4.94 (s,0.51H), 4.90 (s, 0.49H), 3.71 (s, 1.53H), 3.64 (br s, 2.47H), 3.45-3.35(m, 1H), 3.13-3.05 (m, 2H), 2.83 (apparent d, J = 4.5 Hz, 3H), 2.67-2.55(m, 1H), 2.49-2.40 (m, 3H, partially obscured by solvent peak),2.30-2.22 (m, 1H), 2.08-2.01 (m, 1H), 1.64-1.51 (m, 3H), 1.32- 1.23 (m,28H), 0.85 (t, J = 6.6 Hz, 3H) A44

654 ¹H NMR (300 MHz, DMSO-d₆) δ 9.17 (br s, 1H), 6.85 (d, J = 8.4 Hz,1H), 6.75 (d, J = 8.4 Hz, 1H), 6.29 (br s, 1H), 5.58 (dd, J = 5.7, 1.8Hz, 1H), 5.10 (q, J = 6.9 Hz, 1H), 4.99 (s, 1H), 3.75 (s, 3H), 3.64 (brs, 1H), 3.43 (d, J = 19.5 Hz, 1H), 3.16-3.07 (m, 2H), 2.84 (s, 3H),2.64-2.57 (m, 1H), 2.49-2.42 (m, 1H, partially obscured by solventpeak), 2.06 (d, J = 18.0 Hz, 1H), 1.66-1.51 (m, 3H), 1.49 (d, J = 6.9Hz, 3H), 1.32-1.23 (m, 28H), 0.85 (t, J = 6.6 Hz, 3H) A45

652 ¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (br s, 1H), 6.85 (d, J = 8.4 Hz,1H), 6.75 (d, J = 8.4 Hz, 1H), 6.39 (br s, 1H), 5.58-5.56 (m, 1H),5.37-5.27 (m, 2H), 5.10 (q, J = 6.9 Hz, 1H), 4.99 (s, 1H), 3.75 (s, 3H),3.68 (d, J = 6.0 Hz, 1H), 3.43 (d, J = 19.8 Hz, 1H), 3.16-3.07 (m, 2H),2.85 (s, 3H), 2.64-2.58 (m, 1H), 2.49-2.42 (m, 1H, partially obscured bysolvent peak), 2.39-2.27 (m, 3H), 2.09-1.97 (m, 5H), 1.63 (d, J = 11.7Hz, 1H), 1.54- 1.48 (m, 5H), 1.26-1.24 (m, 20H), 0.85 (t, J = 6.3 Hz,3H) A46

532 ¹H NMR (300 MHz, DMSO-d₆) δ 12.71 (br s, 1H), 12.32 (br s, 1H), 9.17(br s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.30 (s,1H), 5.59 (dd, J = 5.7, 1.8 Hz, 1H), 5.42 (t, J = 5.4 Hz, 1H), 4.96 (s,1H), 3.75 (s, 3H), 3.65 (d, J = 6.0 Hz, 1H), 3.16-3.07 (m, 3H),2.90-2.84 (m, 5H), 2.73-2.59 (m, 3H), 2.33-2.25 (m, 1H), 2.07 (d, J =18.0 Hz, 1H), 1.64 (d, J = 11.4 Hz, 1H), three protons obscured bysolvent peaks A47

517 ¹H NMR (300 MHz, DMSO-d₆) δ 12.81 (br s, 1H), 9.17 (br s, 1H), 7.85(d, J = 8.1 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H),6.27 (s, 1H), 5.55-5.53 (m, 2H), 5.00 (s, 1H), 4.35-4.27 (m, 1H), 4.00(q, J = 6.9 Hz, 1H), 3.75 (s, 3H), 3.64 (d, J = 6.0 Hz, 1H), 3.15-3.06(m, 2H), 2.84 (d, J = 4.2 Hz, 3H), 2.7-2.55 (m, 1H), 2.32-2.24 (m, 1H),2.14- 1.89 (m, 3H), 1.63 (d, J = 11.4 Hz, 1H), 1.22 (d, J = 6.9 Hz, 3H),four protons obscured by sovent peaks A48

564 ¹H NMR (300 MHz, CDCl₃) δ 9.15 (br s, 1H), 7.59-7.54 (m, 2H),7.49-7.76 (m, 3H), 6.82 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H),6.30 (br s, 1H), 6.22 (s, 1H), 5.53 (dd, J = 6.0, 1.8 Hz, 1H), 5.15 (q,J = 6.9 Hz, 1H), 4.95 (s, 1H), 3.64 (s, 3H), 3.41 (d, J = 19.8 Hz, 1H),3.14-3.05 (m, 2H), 2.83 (d, J = 4.8 Hz, 3H), 2.70-2.53 (m, 1H),2.46-2.38 (m, 1H), 2.30- 2.22 (m, 1H), 2.08 (s, 3H), 2.06-2.00 (m, 1H),1.62 (d, J = 11.1 Hz, 1H), 1.53 (d, J = 6.9 Hz, 3H) A49

698 ¹H NMR (300 MHz, DMSO-d₆) δ 12.76 (br s, 1H), 9.17 (br s, 1H), 6.84(d, J = 8.1 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.31 (s, 1H), 5.59 (dd, J= 6.0, 3.9 Hz, 1H), 5.41 (t, J = 6.3 Hz, 1H), 4.96 (s, 1H), 3.75 (s,3H), 3.65 (d, J = 6.3 Hz, 1H), 3.13-3.06 (m, 2H), 2.90-2.84 (m, 5H),2.70-2.52 (m, 2H), 2.33 (t, J = 7.2 Hz, 2H), 2.27-2.25 (m, 1H), 1.64 (d,J = 11.7 Hz, 1H), 1.56-1.51 (m, 2H), 1.23 (br s, 30H), 0.88 (t, J = 6.3Hz, 3H) A50

430 ¹H NMR (300 MHz, CDCl₃) δ 9.18 (br s, 1H), 6.86 (d, J = 8.4 Hz, 1H),6.75 (d, J = 8.1 Hz, 1H), 6.31 (s, 1H), 5.58 (dd, J = 5.7, 1.8 Hz, 1H),5.09 (q, J = 6.9 Hz, 1H), 4.99 (s, 1H), 3.76 (s, 3H), 3.65 (d, J = 6.0Hz, 1H), 3.43 (d, J = 20.1 Hz, 1H), 3.16-3.07 (m, 2H), 2.84 (d, J = 4.8Hz, 3H), 2.72-2.52 (m, 1H), 2.49-2.43 (m, 1H, partially obscured bysolvent peak), 2.29 (dd, J = 18.0, 6.6 Hz, 1H), 2.10 (s, 3H), 2.30-2.22(m, 1H), 1.65 (d, J = 11.4 Hz, 1H), 1.49 (d, J = 6.9 Hz, 3H) A51

502 ¹H NMR (300 MHz, CDCl₃) δ 9.17 (br s, 1H), 6.86 (d, J = 8.1 Hz, 1H),6.75 (d, J = 8.4 Hz, 1H), 6.30 (s, 1H), 5.59 (dd, J = 5.7, 1.8 Hz, 1H),5.24 (q, J = 6.9 Hz, 1H), 5.07 (q, J = 7.2 Hz, 1H), 4.99 (s, 1H), 3.75(s, 3H), 3.65 (d, 6.0 Hz, 1H), 3.16-3.07 (m, 2H), 2.84 (d, J = 4.8 Hz,3H), 2.72-2.58 (m, 1H), 2.44-2.40 (m, 1H), 2.30 (dd, J = 18.3, 6.0 Hz,1H), 2.08 (s, 3H), 2.12-2.02 (m, 1H), 1.65 (d, J = 13.2 Hz, 1H), 1.53(d, J = 6.9 Hz, 3H), 1.47 (d, J = 6.9 Hz, 3H), one proton obscured bythe solvent peaks A52

488 ¹H NMR (300 MHz, DMSO-d₆) δ 13.02 (br s, 1H), 9.18 (br s, 1H), 6.86(d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.28 (br s, 1H), 5.53(dd, J = 6.0, 1.8 Hz, 1H), 4.98 (s, 1H), 4.92 (q, J = 6.9 Hz, 1H), 3.75(s, 3H), 3.64 (d, J = 6.3 Hz, 1H), 3.43 (d, J = 19.8 Hz, 1H), 3.15-3.06(m, 2H), 2.84 (d, J = 3.9 Hz, 3H), 2.73-2.58 (m, 5H), 2.46-2.40 (m, 1H),2.32-2.20 (m, 1H), 2.05 (d, J = 18.3 Hz, 1H), 1.64 (d, J = 11.1 Hz, 1H),1.40 (d, J = 6.9 Hz, 3H) A53

724 ¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (br s, 1H), 6.85 (d, J = 8.4 Hz,1H), 6.75 (d, J = 8.4 Hz, 1H), 6.34 (br s, 1H), 5.59-5.58 (m, 1H),5.37-5.30 (m, 2H), 5.24 (q, J = 6.9 Hz, 1H), 5.08 (q, J = 6.9 Hz, 1H),4.99 (s, 1H), 3.75 (s, 3H), 3.65 (br s, 1H), 3.42 (d, J = 20.1 Hz, 1H),3.15-3.06 (m, 2H), 2.84 (s, 3H), 2.64-2.58 (m, 1H), 2.49-2.43 (m, 1H,partially obscured by solvent peak), 2.37-2.26 (m, 3H), 2.09-1.95 (m,5H), 1.63 (d, J = 11.7 Hz, 1H), 1.54-1.45 (m, 8H), 1.26- 1.24 (m, 20H),0.85 (t, J = 6.3 Hz, 3H) A54

532 ¹H NMR (300 MHz, DMSO-d₆) δ 13.23 (br s, 1H), 12.59 (br s, 1H), 9.17(br s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.27 (s,1H), 5.53 (dd, J = 6.3, 2.1 Hz, 1H), 5.22 (dd, J = 7.8, 4.5 Hz, 1H),4.99 (s, 1H), 3.75 (s, 3H), 3.64 (d, J = 6.3 Hz, 1H), 3.46-3.39 (m, 1H,partially obscured by water peak), 3.15-3.06 (m, 2H), 2.84 (s, 3H),2.80-2.66 (m, 7H), 2.49-2.43 (m, 1H, partially obscured by solventpeak), 2.27 (dd, J = 17.7, 6.3 Hz, 1H), 2.06 (apparent d, J = 18.0 Hz,1H), 1.64 (d, J = 11.7 Hz, 1H) A55

474 ¹H NMR (300 MHz, DMSO-d₆) δ 13.38 (br s, 1H), 9.17 (br s, 1H), 6.86(d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.29 (s, 1H), 5.56 (dd, J= 5.7, 1.8 Hz, 1H), 5.26 (dd, J = 8.4, 4.2 Hz, 1H), 4.99 (s, 1H), 3.74(s, 3H), 3.65 (d, J = 6.3 Hz, 1H), 3.4 (d, J = 20.1 Hz, 1H, partiallyobscured by water peak), 3.16-3.06 (m, 3H), 2.98 (dd, J = 16.8, 8.4 Hz,1H), 2.84 (apparent d, J = 3.9 Hz, 3H), 2.65- 2.57 (m, 1H), 2.49-2.42(m, 1H, partially obscured by solvent peak), 2.28 (dd, J = 17.7. 6.3 Hz,1H), 2.09 (s, 3H), 2.09-2.04 (m, 1H), 1.65 (d, J = 11.1 Hz, 1H) A56

550 ¹H NMR (300 MHz, DMSO-d₆) δ 13.29 (br s, 1H), 9.18 (br s, 1H),7.46-7.40 (m, 5H), 6.86 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H),6.29 (br s, 1H), 5.84 (s, 1H), 5.50- 5.46 (m, H), 4.96 (s, 1H), 3.74 (s,3H), 3.64 (d, J = 6.0 Hz, 1H), 3.43 (d, J = 19.8 Hz, 1H), 3.15-3.06 (m,2H), 2.84 (apparent d, J = 3.3 Hz, 3H), 2.76 (s, 4H), 2.65-2.58 (m, 1H),2.43 (dd, J = 12.9, 4.2 Hz, 1H), 2.26 (dd, J = 17.7, 6.0 Hz, 1H), 2.04(apparent d, J = 17.7 Hz, 1H), 1.63 (d, J = 12.0 Hz, 1H) A57

564 ¹H NMR (300 MHz, DMSO-d₆) δ 9.19 (br s, 1H), 7.52-7.48 (m, 2H),7.42- 7.37 (m, 3H), 6.86 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H),6.28 (s, 1H), 6.06 (s, 1H), 5.47 (dd, J = 5.7, 1.8 Hz, 1H), 5.28 (q, J =6.9 Hz, 1H), 4.82 (s, 1H), 3.73 (s, 3H), 3.64 (d, J = 6.0 Hz, 1H), 3.42(d, J = 20.1 Hz, 1H), 3.15-3.06 (m, 2H), 2.84 (apparent d, J = 4.8 Hz,3H), 2.68- 2.57 (m, 1H), 2.49-2.35 (m, 1H, partially obscured by solventpeak), 2.27 (dd, J = 18.0, 6.0 Hz, 1H), 2.14 (s, 3H), 2.04 (apparent d,J = 17.7 Hz, 1H), 1.62 (d, J = 12.0 Hz, 1H), 1.48 (d, J = 6.9 Hz, 3H)A58

530 ¹H NMR (300 MHz, DMSO-d₆) δ 6.81 (d, J = 8.1 Hz, 1H), 6.70 (d, J =8.1 Hz, 1H), 5.53 (dd, J = 5.7, 2.1 Hz, 1H), 5.09-5.06 (m, 1H), 4.93 (s,1H), 3.74 (s, 3H), 3.28 (d, J = 18.9 Hz, 1H), 2.83-2.61 (m, 9H),2.37-2.13 (m, 6H), 2.02 (d, J = 18 Hz, 1H), 1.52 (d, J = 9.9 Hz, 1H),two CO₂H and OH protons not observed A59

504 ¹H NMR (300 MHz, DMSO-d₆) δ 6.75 (d, J = 8.4 Hz, 1H), 6.66 (d, J =8.4 Hz, 1H), 5.91 (s, 1H), 5.52 (dd, J = 5.7, 2.4 Hz, 1H), 4.95 (dd, J =13.8, 6.9 Hz, 1H), 4.86 (s, 1H), 4.49-4.47 (m, 1H), 3.74 (s, 3H), 3.13(d, J = 18.9 Hz, 1H), 2.97-2.89 (m, 2H), 2.69-2.61 (m, 2H), 2.46-2.42(m, 1H), 2.28-2.22 (m, 2H), 2.12-2.00 (m, 4H), 1.42-1.36 (m, 4H), CO₂Hand OH protons not observed A60a

602 ¹H NMR (300 MHz, DMSO-d₆) δ 6.73 (d, J = 8.4 Hz, 1H), 6.65 (d, J =8.1 Hz, 1H), 5.55 (dd, J = 5.4, 2.4 Hz, 1H), 5.21-5.13 (m, 2H), 4.83 (s,1H), 4.72 (s, 1H), 3.73 (s, 3H), 3.10 (d, J = 18.6 Hz, 1H), 2.97-2.94(m, 2H), 2.83 (d, J = 6.0 Hz, 1H), 2.60 (dd, J = 18.9, 6.0 Hz, 1H), 2.41(dd, J = 11.4, 3.9 Hz, 1H), 2.31 (s, 3H), 2.22 (dd, J = 12.6, 4.8 Hz,1H), 2.10-1.94 (m, 3H), 2.04 (s, 3H), 1.49 (d, J = 6.9 Hz, 3H) 1.41 (s,9H), 1.39 (d, J = 12.3 Hz, 1H) A60b

546 ¹H NMR (300 MHz, DMSO-d₆) δ 13.37 (br s, 1H), 9.18 (br s, 1H), 6.85(d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.30 (s, 1H), 5.59 (dd, J= 5.7, 1.8 Hz, 1H), 5.27 (dd, J = 7.8, 4.5 Hz, 1H), 5.18 (q, J = 7.2 Hz,1H), 5.00 (s, 1H), 3.75 (s, 3H), 3.65 (d, J = 6.3 Hz, 1H), 3.43 (d, J =19.8 Hz, 1H, partially obscured by water peak), 3.16-3.07 (m, 2H),3.05-2.90 (m, 2H), 2.84 (apparent d, J = 3.0 Hz, 3H), 2.66-2.55 (m, 1H),2.49-2.43 (m, 1H, partially obscured by solvent peak), 2.34-2.26 (m,1H), 2.10-2.04 (m, 1H), 2.04 (s, 3H), 1.65 (d, J = 11.1 Hz, 1H), 1.50(d, J = 7.2 Hz, 3H) A61

532 ¹H NMR (300 MHz, DMSO-d₆) δ 13.87 (br s, 1H), 9.17 (br s, 1H), 6.88(d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.34 (s, 1H), 5.77 (d, J= 3.0 Hz, 1H), 5.68 (d, J = 3.0 Hz, 1H), 5.56 (dd, J = 6.3, 2.1 Hz, 1H),4.88 (s, 1H), 3.76 (s, 3H), 3.65 (d, J = 6.3 Hz, 1H), 3.43 (d, J = 20.1Hz, 1H), 3.16-3.07 (m, 2H), 2.84 (apparent d, J = 3.3 Hz, 3H), 2.64-2.57(m, 1H), 2.49-2.43 (m, 1H, partially obscured by solvent peak),2.33-2.25 (m, 1H), 2.18 (s, 3H), 2.14 (s, 3H), 2.11-2.05 (m, 1H), 1.65(d, J = 11.4 Hz, 1H) A62

608 ¹H NMR (300 MHz, DMSO-d6; Mixture of diastereomers) δ 7.58- 7.53 (m,2H), 7.48-7.44 (m, 3H), 6.75-6.71 (m, 0.8H), 6.69-6.64 (m, 1.2H), 6.21(s, 0.4H), 6.12 (s, 0.6H), 5.53-5.47 (m, 0.8H), 5.45-5.43 (m, 1.2H),4.81 (s, 0.6H), 4.78 (s, 0.4H), 3.70 (s, 1.8H), 3.60 (s, 1.2H), 3.12 (d,J = 18.3 Hz, 1H), 3.00-3.72 (m, 5H), 2.46-2.42 (m, 1H), 2.35 (s, 3H),2.28-1.99 (m, 6H), 1.38 (d, J = 12.6 Hz, 1H), CO₂H, CF₃CO₂H, and OHprotons not observed A63

546 ¹H NMR (300 MHz, DMSO-d₆) δ 6.81 (d, J = 8.4 Hz, 1H), 6.71 (d, J =8.4 Hz, 1H), 5.57 (dd, J = 5.7, 2.1 Hz, 1H), 5.39 (dd, J = 9.6, 3.2 Hz,1H), 5.04 (dd, J = 14.1. 6.9 Hz, 1H), 4.95 (s, 1H), 3.73 (s, 3H),3.29-3.26 (m, 1H), 3.17 (d, J = 17.1 Hz, 1H), 3.00- 2.72 (m, 3H),2.64-2.62 (m, 3H), 2.39-2.37 (m, 3H), 2.22-2.00 (m, 2H), 2.11 (s, 3H),1.53 (d, J = 9.9 Hz, 1H), 1.43 (d, J = 6.9 Hz, 3H), CO₂H, CF₃CO₂H, andOH protons not observed A64

546 ¹H NMR (300 MHz, DMSO-d₆) δ 6.77 (d, J = 8.4 Hz, 1H), 6.68 (d, J =8.4 Hz, 1H), 5.61 (dd, J = 5.7, 2.4 Hz, 1H), 5.45 (dd, J = 6.9, 2.1 Hz,1H), 4.99 (dd, J = 14.1, 6.9 Hz, 1H), 4.87 (s, 1H), 3.74 (s, 3H), 3.19(d, J = 19.2 Hz, 1H), 3.12-2.99 (m, 5H), 2.79- 2.59 (m, 2H), 2.47-2.46(m, 1H), 2.37-1.97 (m, 7H), 1.45 (d, J = 12.6 Hz, 1H), 1.40 (d, J = 7.2Hz, 3H), CO₂H, CF₃CO₂H, and OH protons not observed A65

546 ¹H NMR (300 MHz, DMSO-d₆) δ 12.8 (s, 1H), 9.19 (s, 1H), 6.86 (d, J =8.4 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.31 (s, 1H), 5.59 (dd, J = 6.0,1.8 Hz, 1H), 5.36 (dd, J = 9.0, 3.6 Hz, 1H), 5.26 (dd, J = 14.1, 6.9 Hz,1H), 5.00 (s, 1H), 3.75 (s, 3H), 3.65 (d, J = 6.3 Hz, 1H), 3.43 (d, J =20.1 Hz, 1H), 3.16-3.07 (m, 2H), 2.96-2.72 (m, 5H), 2.62-2.52 (m, 1H),2.46- 2.42 (m, 1H), 2.34-2.26 (m, 1H), 2.09 (s, 3H), 2.06 (d, J = 16.0Hz, 1H), 1.64 (d, J = 11.1 Hz, 1H), 1.52 (d, J = 6.9 Hz, 3H) A66

666 ¹H NMR (300 MHz, DMSO-d₆) δ 13.5 (s, 1H), 9.18 (s, 1H), 7.46-7.41(m, 5H), 6.88 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.35 (s,1H), 6.01 (s, 1H), 5.92 (dd, J = 24.6, 2.7 Hz, 1H), 5.55 (dd, J = 6.0,2.1 Hz, 1H), 4.87 (s, 1H), 3.75 (s, 3H), 3.65 (d, J = 6.0 Hz, 1H), 3.43(d, J = 20.1 Hz, 1H), 3.16-3.07 (m, 2H), 2.84 (d, J = 3.6 Hz, 3H),2.64-2.61 (m, 1H), 2.41- 2.32 (m, 2H), 2.32-2.27 (m, 1H), 2.20 (s, 3H),2.08 (d, J = 18.3 Hz, 1H), 2.00 (s, 3H), 1.64 (d, J = 11.7 Hz, 1H) A67

532 ¹H NMR (300 MHz, DMSO-d₆) δ 13.87 (br s, 1H), 9.18 (br s, 1H), 6.84(d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.33 (s, 1H), 5.80 (d, J= 3.0 Hz, 1H), 5.59 (dd, J = 5.7, 1.8 Hz, 1H), 5.56 (d, J = 3.0 Hz, 1H),5.00 (s, 1H), 3.72 (s, 3H), 3.65 (d, J = 6.3 Hz, 1H), 3.43 (d, J = 19.8Hz, 1H), 3.16- 3.07 (m, 2H), 2.84 (apparent d, J = 2.7 Hz, 3H),2.65-2.58 (m, 1H), 2.49-2.43 (m, 1H, partially obscured by solventpeak), 2.34-2.25 (m, 1H), 2.17 (s, 3H), 2.15 (s, 3H), 2.11-2.05 (m, 1H),1.66 (d, J = 10.8 Hz, 1H) A68a

504 ¹H NMR (300 MHz, DMSO-d₆) δ 13.42 (br s, 1H), 9.18 (br s, 1H), 6.86(d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.29 (s, 1H), 5.56-5.55(m, 1H), 5.46 (br s, 1H), 5.31 (dd, J = 8.1, 4.2 Hz, 1H), 4.99 (s, 1H),4.21 (q, J = 6.9 Hz, 1H), 3.75 (s, 3H), 3.64 (d, J = 6.3 Hz, 1H),3.48-3.40 (m, 1H, partially obscured by water peak), 3.15-2.96 (m, 4H),2.84 (apparent d, J = 4.2 Hz, 3H), 2.66-2.58 (m, 1H), 2.49-2.42 (m, 1H,partially obscured by solvent peak), 2.32-2.24 (m, 1H), 2.07 (apparentd, J = 18.0 Hz, 1H), 1.64 (d, J = 11.7 Hz, 1H), 1.31 (d, J = 6.9 Hz, 3H)A68b

560 ¹H NMR (300 MHz, CDCl₃) δ 9.18 (br s, 1H), 6.86 (d, J = 8.4 Hz, 1H),6.75 (d, J = 8.4 Hz, 1H), 6.27 (s, 1H), 5.56-5.54 (m, 1H), 5.48 (br s,1H), 5.24 (dd, J = 7.5, 4.8 Hz, 1H), 4.99 (s, 1H), 4.21 (q, J = 6.6 Hz,1H), 3.74 (s, 3H), 3.64 (d, J = 6.0 Hz, 1H), 3.46-3.40 (m, 1H, partiallyobscured by water peak), 3.15-2.97 (m, 4H), 2.85 (apparent d, J = 4.8Hz, 3H), 2.66-2.57 (m, 1H), 2.49-2.42 (m, 1H, partially obscured bysolvent peak), 2.33-2.24 (m, 1H), 2.07 (apparent d, J = 18.3 Hz, 1H),1.64 (d, J = 12.0 Hz, 1H), 1.41 (s, 9H), 1.32 (d, J = 6.9 Hz, 3H) A69

432 ¹H NMR (300 MHz, DMSO-d₆) δ 12.7 (s, 1H), 9.19 (s, 1H), 6.86 (d, J =8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.28 (s, 1H), 5.63 (s, 1H),5.53-5.51 (m, 1H), 4.98 (s, 1H), 4.34 (dd, J = 7.8, 2.1 Hz, 1H), 3.76(s, 3H), 3.64 (d, J = 6.3 Hz, 1H), 3.43 (d, J = 20.1 Hz, 1H), 3.15-3.07(m, 2H), 2.89- 2.82 (m, 4H), 2.72-2.61 (m, 2H), 2.46-2.42 (m, 1H),2.33-2.26 (m, 1H), 2.05 (d, J = 18.0 Hz, 1H), 1.64 (d, J = 11.5 Hz, 1H)A70

517 ¹H NMR (300 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.29 (s, 3H), 6.86 (d, J =8.4 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.34 (s, 1H), 5.60-5.58 (m, 1H),5.14 (dd, J = 13.8, 7.2 Hz, 1H), 5.00 (s, 1H), 3.76 (s, 3H), 3.66 (d, J= 6.3 Hz, 1H), 3.43 (d, J = 20.1 Hz, 1H), 3.16- 3.07 (m, 2H), 2.85 (s,3H), 2.72-2.61 (m, 3H), 2.46-2.42 (m, 1H), 2.33- 2.26 (m, 1H), 2.15-1.99(m, 3H), 2.07 (d, J = 18.0 Hz, 1H), 1.64 (d, J = 11.5 Hz, 1H), 1.51 (d,J = 7.2 Hz, 3H), CO₂H proton not observed A71

608 ¹H NMR (300 MHz, DMSO-d₆) δ 13.40 (br s, 1H), 9.16 (br s, 1H),7.57-7.54 (m, 2H), 7.48-7.46 (m, 3H), 6.81 (d, J = 8.4 Hz, 1H), 6.73 (d,J = 8.4 Hz, 1H), 6.29 (s, 1H), 6.17 (s, 1H), 5.55 (dd, J = 6.0, 2.1 Hz,1H), 5.33 (dd, J = 8.7, 3.9 Hz, 1H), 4.95 (s, 1H), 3.75 (br s, 4H),3.44-3.38 (m, 1H, partially obscured by water peak), 3.14-2.97 (m, 4H),2.83 (apparent d, J = 4.2 Hz, 3H), 2.68- 2.57 (m, 1H), 2.49-2.40 (m, 1H,partially obscured by solvent peak), 2.31-2.22 (m, 1H), 2.09-2.04 (m,1H), 2.04 (s, 3H), 1.63 (d, J = 12.0 Hz, 3H) A72

648 ¹H NMR (300 MHz, DMSO-d₆) δ 13.5 (s, 1H), 12.6 (s, 1H), 9.18 (s,1H), 6.88 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.34 (s, 1H),5.85 (d, J = 2.7 Hz, 1H), 5.78 (d, J = 2.7 Hz, 1H), 5.55 (dd, J = 6.0.2.1 Hz, 1H), 5.30 (dd, J = 8.4, 3.6 Hz, 1H), 4.88 (s, 1H), 3.75 (s, 3H),3.65 (d, J = 6.0 Hz, 1H), 3.43 (d, J = 20.1 Hz, 1H), 3.16-3.07 (m, 2H),2.90-2.80 (m, 5H), 2.64- 2.61 (m, 1H), 2.41-2.32 (m, 1H), 2.32-2.27 (m,1H), 2.20 (s, 3H), 2.12 (s, 3H), 2.08 (d, J = 18.3 Hz, 1H), 1.64 (d, J =11.7 Hz, 1H) A73

548 ¹H NMR (300 MHz, DMSO-d₆) δ 13.41 (br s, 1H), 12.69 (br s, 1H), 9.19(br s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.31 (brs, 1H), 5.57 (dd, J = 5.7, 1.5 Hz, 1H), 5.55 (br s, 1H), 5.30 (dd, J =7.8, 4.5 Hz, 1H), 4.99 (s, 1H), 4.2 (dd, J = 7.8, 4.2 Hz, 1H), 3.75 (s,3H), 3.65 (d, J = 6.3 Hz, 1H), 3.43 (d, J = 20.1 Hz, 1H), 3.16-2.95 (m,4H), 2.84 (s, 3H), 2.81-2.58 (m, 3H), 2.49-2.43 (m, 1H, partiallyobscured by solvent peak), 2.32-2.24 (m, 1H), 2.07 (apparent d, J = 18.0Hz, 1H), 1.64 (d, J = 11.1 Hz, 1H) A74

556 ¹H NMR (300 MHz, DMSO-d₆) δ 9.20 (br s, 2H), 8.61 (t, J = 5.7 Hz,1H), 8.54 (br s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.1 Hz,1H), 6.31 (br s, 1H), 5.59 (dd, J = 6.0, 2.1 Hz, 1H), 5.12 (q, J = 7.2Hz, 1H), 5.00 (s, 1H), 4.13-4.09 (m, 1H), 3.76 (s, 3H), 3.66 (d, J = 6.0Hz, 1H), 3.51-3.29 (m, 4H), 3.22-3.07 (m, 4H), 2.85 (apparent d, J = 4.5Hz, 3H), 2.70- 2.58 (m, 2H), 2.49-2.41 (m, 1H, partially obscured bysolvent peak), 2.34-2.19 (m, 2H), 2.06 (apparent d, J = 18.0 Hz, 1H),1.92-1.77 (m, 3H), 1.64 (d, J = 11.1 Hz, 1H), 1.51 (d, J = 6.9 Hz, 3H)A75

629 ¹H NMR (300 MHz, DMSO-d₆) δ 9.19 (br s, 1H), 8.05-7.98 (m, 2H), 7.65(br s, 3H), 6.86 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.32 (s,1H), 5.59 (dd, J = 5.7, 1.8 Hz, 1H), 5.10 (q, J = 6.9 Hz, 1H), 5.00 (s,1H), 4.19-4.12 (m, 1H), 3.75 (s, 3H), 3.66 (d, J = 6.0 Hz, 1H), 3.43 (d,J = 19.8 Hz, 1H), 3.35-3.25 (m, 2H), 3.16- 3.07 (m, 2H), 2.85 (apparentd, J = 4.5 Hz, 3H), 2.79-2.70 (m, 2H), 2.65-2.53 (m, 3H, partiallyobscured by solvent peak), 2.49-2.43 (m, 1H, partially obscured bysolvent peak), 2.34-2.26 (m, 1H), 2.06 (apparent d, J = 18.3 Hz, 1H),1.84 (s, 3H), 1.67- 1.40 (m, 8H), 1.33-1.20 (m, 2H) A76

560 ¹H NMR (300 MHz, DMSO-d₆) δ 12.28 (br s, 1H), 9.19 (br s, 1H), 6.85(d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 5.61 (dd, J= 5.7, 1.8 Hz, 1H), 5.47 (t, J = 5.4 Hz, 1H), 4.96 (s, 1H), 4.13 (q, J =6.9 Hz, 2H), 3.74 (s, 3H), 3.65 (d, J = 6.0 Hz, 1H), 3.43 (d, J = 19.8Hz, 1H), 3.16- 3.07 (m, 2H), 2.98 (d, J = 6.6 Hz, 2H), 2.84 (apparent d,J = 4.8 Hz, 3H), 2.69-2.58 (m, 3H), 2.49-2.43 (m, 1H, partially obscuredby solvent peak), 2.34-2.26 (m, 1H), 2.07 (apparent d, J = 18.3 Hz, 1H),1.65 (d, J = 10.8 Hz, 1H), 1.21 (t, J = 6.9 Hz, 3H), two protonsobscured by the solvent peaks A77

572 ¹H NMR (300 MHz, DMSO-d₆) δ 9.19 (br s, 1H), 8.63 (t, J = 5.4 Hz,1H), 8.11 (br s, 3H), 6.86 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz,1H), 6.32 (br s, 1H), 5.59 (dd, J = 5.7, 1.8 Hz, 1H), 5.13 (q, J = 6.9Hz, 1H), 5.00 (s, 1H), 3.76 (s, 3H), 3.67-3.65 (m, 2H), 3.53-3.40 (m,2H), 3.35-3.24 (m, 1H), 3.16-3.07 (m, 2H), 2.85 (apparent d, J = 4.5 Hz,3H), 2.73- 2.59 (m, 3H), 2.49-2.43 (m, 1H, partially obscured by solventpeak), 2.34-2.26 (m, 1H), 2.06 (apparent d, J = 18.3 Hz, 1H), 1.66-1.50(m, 7H), 0.90-0.87 (m, 6H) A78

448 ¹H NMR (300 MHz, DMSO-d₆) δ 12.8 (s, 1H), 9.20 (s, 1H), 6.86 (d, J =8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.30 (s, 1H), 5.71 (s, 1H), 5.54(dd, J = 6.0, 2.1 Hz, 1H), 5.31 (s, 1H), 5.04 (s, 1H), 4.55 (s, 1H),4.41 (s, 1H), 3.75 (s, 3H), 3.64 (d, J = 6.3 Hz, 1H), 3.43 (d, J = 19.8Hz, 1H), 3.15-3.07 (m, 2H), 2.85 (d, J = 3.3 Hz, 3H), 2.69-2.62 (m, 1H),2.49-2.43 (m, 1H), 2.32-2.26 (m, 1H), 2.07 (d, J = 18.3 Hz, 1H), 1.65(d, J = 11.1 Hz, 1H) A79

556 ¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (s, 2H), 8.96 (d, J = 6.6 Hz, 1H),8.55 (s, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.30(s, 1H), 5.59 (dd, J = 6.0, 2.1 Hz, 1H), 5.19 (dd, J = 14, 7.2 Hz, 1H),4.99 (s, 1H), 4.48- 4.39 (m, 1H), 4.25-4.18 (m, 1H), 3.76 (s, 3H), 3.66(d, J = 6.0 Hz, 1H), 3.43 (d, J = 19.8 Hz, 1H), 3.23-3.07 (m, 4H), 2.85(d, J = 4.5 Hz, 3H), 2.69- 2.57 (m, 1H), 2.49-2.41 (m, 1H), 2.33-2.26(m, 2H), 2.06 (d, J = 18 Hz, 1H), 1.93-1.84 (m, 3H), 1.64 (d, J = 11.1Hz, 1H), 1.52 (d, J = 6.9 Hz, 3H), 1.41 (d, J = 7.2 Hz, 3H) A80

604 ¹H NMR (300 MHz, DMSO-d₆) δ 13.2 (s, 1H), 9.17 (s, 1H), 6.88 (d, J =8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.35 (s, 1H), 5.87 (dd, J = 13.5,2.7 Hz, 2H), 5.57 (dd, J = 6.3, 2.1 Hz, 1H), 5.04 (dd, J = 13.8, 1.2 Hz,1H), 4.88 (s, 1H), 3.76 (s, 3H), 3.65 (d, J = 6.3 Hz, 1H), 3.41 (d, J =20.1 Hz, 1H), 3.16-3.07 (m, 2H), 2.84 (d, J = 3.6 Hz, 3H), 2.64-2.61 (m,1H), 2.46-2.42 (m, 1H), 2.33-2.26 (m, 1H), 2.21 (s, 3H), 2.15 (s, 3H),2.08 (d, J = 18.0 Hz, 1H), 164 (d, J = 11.1 Hz, 1H), 1.38 (d, J = 7.2Hz, 3H) A81

629 ¹H NMR (300 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.42 (d, J = 6.6 Hz, 1H),8.00 (d, J = 8.4 Hz, 1H), 7.64 (s, 3H), 6.86 (d, J = 8.4 Hz, 1H), 6.76(d, J = 8.4 Hz, 1H), 6.30 (s, 1H), 5.57 (dd, J = 6.0, 2.1 Hz, 1H), 5.15(dd, J = 14, 6.9 Hz, 1H), 4.99 (s, 1H), 4.34-4.25 (m, 2H), 3.75 (s, 3H),3.66 (d, J = 6.0 Hz, 1H), 3.43 (d, J = 19.8 Hz, 1H), 3.16- 3.07 (m, 2H),2.85 (d, J = 4.5 Hz, 3H), 2.76-2.62 (m, 2H), 2.33-2.26 (m, 2H), 2.06 (d,J = 18 Hz, 1H), 1.84 (s, 3H), 1.66-1.34 (m, 14H) A82

504 ¹H NMR (300 MHz, DMSO-d₆) δ 13.1 (s, 1H), 9.17 (s, 1H), 6.87 (d, J =8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.29 (s, 1H), 6.00 (s, 1H), 5.57(dd, J = 6.0, 1.8 Hz, 1H), 4.98 (d, J = 4.5 Hz, 1H), 4.96 (dd, J = 14.1,6.9 Hz, 1H), 4.54-4.50 (m, 1H), 3.76 (s, 3H), 3.64 (d, J = 5.7 Hz, 1H),3.43 (d, J = 20.1 Hz, 1H), 3.16-3.07 (m, 2H), 2.85-2.78 (m, 5H),2.65-2.61 (m, 1H), 2.46-2.42 (m, 1H), 2.33-2.25 (m, 1H), 2.07 (d, J =18.0 Hz, 1H), 1.64 (d, J = 11.1 Hz, 1H), 1.40 (d, J = 6.9 Hz, 3H) A83

604 ¹H NMR (300 MHz, DMSO-d₆) δ 13.9 (s, 1H), 9.19 (s, 1H), 6.85 (d, J =8.1 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.32 (s, 1H), 5.72 (d, J = 3.0Hz, 1H), 5.66-5.60 (m, 2H), 5.29 (dd, J = 13.8, 6.9 Hz, 1H), 5.03 (s,1H), 3.74 (s, 3H), 3.65 (d, J = 6. Hz, 1H), 3.4 (d, J = 20.1 Hz, 1H),3.16-3.07 (m, 2H), 2.84 (d, J = 3.6 Hz, 3H), 2.64-2.61 (m, 1H),2.46-2.42 (m, 1H), 2.33- 2.26 (m, 1H), 2.13 (s, 3H), 2.11 (s, 3H), 2.06(d, J = 18.0 Hz, 1H), 1.65 (d, J = 11.1 Hz, 1H), 1.48 (d, J = 6.9 Hz,3H) A84

648 ¹H NMR (300 MHz, DMSO-d₆) δ 13.5 (s, 1H), 12.7 (s, 1H), 9.17 (s,1H), 6.88 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.33 (s, 1H),5.80 (dd, J = 9.6, 2.7 Hz, 2H), 5.57 (dd, J = 6.0, 2.1 Hz, 1H), 5.35(dd, J = 7.8, 1.2 Hz, 1H), 4.89 (s, 1H), 3.75 (s, 3H), 3.65 (d, J = 6.3Hz, 1H), 3.41 (d, J = 20.1 Hz, 1H), 3.15-3.07 (m, 2H), 2.93- 2.80 (m,5H), 2.64-2.61 (m, 1H), 2.41-2.32 (m, 1H), 2.32-2.26 (m, 1H), 2.27 (s,3H), 2.07 (s, 3H), 2.06 (d, J = 18.3 Hz, 1H), 1.64 (d, J = 11.4 Hz, 1H)A85

503 ¹H NMR (300 MHz, DMSO-d₆) δ 13.2 (s, 1H), 9.20 (s, 1H), 8.48 (s,3H), 6.87 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.32 (s, 1H),5.62-5.59 (m, 1H), 5.39-5.30 (m, 1H), 5.00 (d, J = 7.5 Hz, 1H),4.48-4.45 (m, 1H), 3.76 (s, 3H), 3.66 (d, J = 6.3 Hz, 1H), 3.44 (d, J =20.1 Hz, 1H), 3.16-3.07 (m, 2H), 2.96-2.85 (m, 5H), 2.64- 2.61 (m, 1H),2.46-2.42 (m, 1H), 2.33-2.26 (m, 1H), 2.07 (d, J = 18.0 Hz, 1H), 1.64(d, J = 12.6 Hz, 1H), 1.55 (d, J = 7.2 Hz, 3H) A86

588 ¹H NMR (300 MHz, DMSO-d₆) δ 12.35 (br s, 1H), 9.19 (br s, 1H), 8.61(t, J = 5.4 Hz, 1H), 8.13 (br s, 3H), 6.86 (d, J = 8.4 Hz, 1H), 6.76 (d,J = 8.4 Hz, 1H), 6.31 (br s, 1H), 5.59 (dd, J = 5.7, 1.8 Hz, 1H), 5.12(q, J = 7.2 Hz, 1H), 5.00 (s, 1H), 3.76 (s, 3H), 3.75-3.71 (m, 1H), 3.66(d, J = 6.3 Hz, 1H), 3.53-3.4-0 (m, 3H), 3.35- 3.25 (m, 1H), 3.16-3.07(m, 2H), 2.85 (apparent d, J = 3.6 Hz, 3H), 2.67- 2.55 (m, 2H),2.49-2.42 (m, 1H, partially obscured by solvent peak), 2.35-2.26 (m,3H), 2.09-2.03 (m, 1H), 1.95-1.89 (m, 2H), 1.64 (d, J = 11.1 Hz, 1H),1.51 (d, J = 7.2 Hz, 3H) A87

588 ¹H NMR (300 MHz, DMSO-d₆) δ 9.19 (br s, 1H), 8.26 (br s, 3H), 8.10(t, J = 5.7 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H),6.32 (br s, 1H), 5.58 (dd, J = 5.7, 1.8 Hz, 1H), 5.11 (q, J = 7.2 Hz,1H), 5.00 (s, 1H), 3.93 (br s, 1H), 3.75 (s, 3H), 3.66 (d, J = 6.3 Hz,1H), 3.47-3.40 (m, 2H, partially obscured by water peak), 3.36-3.27 (m,2H), 3.16-3.07 (m, 2H), 2.85 (s, 3H), 2.63-2.55 (m, 2H), 2.49-2.43 (m,1H, partially obscured by solvent peak), 2.34-2.17 (m, 3H), 2.09-1.93(m, 3H), 1.64 (d, J = 11.1 Hz, 1H), 1.50 (d, J = 7.2 Hz, 3H), CO₂Hproton not observed A88

606 ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (br s, 1H), 8.48 (t, J = 5.7 Hz,1H), 8.17 (br s, 3H), 7.37-7.26 (m, 3H), 7.23-7.20 (m, 2H), 6.86 (d, J =8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.29 (br s, 1H), 5.58 (dd, J =6.0, 2.1 Hz, 1H), 5.09 (q, J = 7.2 Hz, 1H), 4.99 (s, 1H), 3.94 (br s,1H), 3.75 (s, 3H), 3.65 (d, J = 6.3 Hz, 1H), 3.45- 3.40 (m, 3H,partially obscured by water peak), 3.24-3.07 (m, 4H), 2.99-2.96 (m, 2H),2.85 (apparent d, J = 4.2 Hz, 3H), 2.68-2.55 (m, 1H), 2.49-2.41 (m, 1H,partially obscured by solvent peak), 2.37-2.25 (m, 1H), 2.05 (apparentd, J = 17.7 Hz, 1 H), 1.64 (d, J = 13.2 Hz, 1H), 1.52 (d, J = 6.9 Hz,3H)

In further embodiments, the abuse-resistant opioid compound may beselected from one or more of:

Ex, Mass No. Structure Spec ¹H NMR Data B1a

636 ¹H NMR (300 MHz, DMSO-d₆) δ 7.54-7.51 (m, 2H), 7.46-7.44 (m, 3H),6.90 (d, J = 8.1 Hz, 0.14H), 6.87 (d, J = 8.1 Hz, 0.86H), 6.72 (d, J =8.4 Hz, 0.14H), 6.71 (d, J = 8.1 Hz, 0.86H), 5.98 (s, 0.14H), 5.97 (s,0.86H), 5.57 (dd, J = 5.4, 2.1 Hz, 0.86H), 5.42-5.41 (m, 0.14H), 4.86(s, 0.86H), 4.83 (s, 0.14H), 4.76 (br s, 1H), 3.14 (d, J = 19.2 Hz, 1H),2.86- 2.84 (m, 1H), 2.69-2.61 (m, 1H), 2.43-2.41 (m, 1H), 2.31 (s, 3H),2.27-2.23 (m, 1H), 2.11-1.94 (m, 3H), 1.47 (s, 1.26H), 1.46 (s, 7.74H),1.43 (s, 9H), 1.39-1.33 (m, 1H) B1b

436 ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.12 (br s, 1H), 7.50-7.47(m, 2H), 7.42-7.31 (m, 3H), 6.68 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 8.1Hz, 1H), 6.26 (d, J = 5.7 Hz, 1H), 6.24 (s, 1H), 5.48-5.45 (m, 1H), 5.27(d, J = 5.4 Hz, 1H), 4.87 (s, 1H), 3.61-3.60 (m, 1H), 3.40-3.34 (m, 1H),3.07-3.01 (m, 2H), 2.82 (d, J = 4.5 Hz, 3H), 2.64-2.57 (m, 1H),2.43-2.38 (m, 1H), 2.28-2.18 (m, 1H), 2.09-2.03 (m, 1H), 1.62-1.58 (m,1H) B2a

574 ¹H NMR (300 MHz, DMSO-d₆) δ 6.88 (d, J = 8.4 Hz, 1H), 6.72 (d, J =8.4 Hz, 1H), 5.58 (dd, J = 5.7, 2.4 Hz, 1H), 4.99-4.92 (m, 2H), 4.78 (s,1H), 3.15 (d, J = 18.9 Hz, 1H), 2.87-2.86 (m, 1H), 2.73-2.62 (m, 1H),2.49- 2.41 (m, 1H), 2.32 (s, 3H), 2.29-2.23 (m, 1H), 2.12-1.95 (m, 2H),1.47- 1.22 (m, 23H) B2b

374 ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s, 1H), 9.19 (br s, 1H), 6.67 (d,J = 8.1 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.21 (br s, 1H), 5.60-5.53(m, 2H), 4.94 (s, 1H), 4.30-4.25 (m, 1H), 3.57 (br s, 1H), 3.04-2.99 (m,2H), 2.79 (s, 3H), 2.65-2.35 (m, 2H), 2.29-2.22 (m, 1H), 2.09-2.02 (m,1H), 1.62- 1.57 (m, 1H), 1.36 (d, J = 6.9 Hz, 3H), one proton obscuredby solvent peaks B3

566 ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s, 1H), 9.15 (br s, 1H), 6.67 (d,J = 8.1 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.22 (s, 1H), 5.51-5.49 (m,1H), 5.34-5.31 (m, 2H), 4.95 (s, 1H), 3.62-3.60 (m, 1H), 3.37 (d, J =19.8 Hz, 1H), 3.11-3.02 (m, 2H), 2.84 (d, J = 4.8 Hz, 3H), 2.78-2.56 (m,1H), 2.45-2.40 (m, 3H), 3.37 (dd, J = 18.0, 6.0 Hz, 1H), 2.08-1.98 (m,5H), 1.63-1.52 (m, 3H), 1.28-1.24 (br m, 20H), 0.85 (t, J = 6.3 Hz, 3H)B4

568 ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 9.14 (br s, 1H), 6.67 (d,J = 8.1 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.21 (s, 1H), 5.52-5.49 (m,1H), 4.95 (s, 1H), 3.62-3.60 (m, 1H), 3.41-3.33 (m, 1H), 3.11-3.02 (m,2H), 2.84 (d, J = 4.8 Hz, 3H), 2.73-2.63 (m, 1H), 2.45-2.40 (m, 3H),2.30-2.22 (m, 1H), 2.08-2.03 (m, 1H), 1.63-1.54 (m, 3H), 1.33-1.24 (brm, 28H), 0.85 (t, J = 6.3 Hz, 3H) B5

418 ¹H NMR (300 MHz, DMSO-d₆) δ 12.7 (br s, 1H), 9.32 (s, 1H), 9.16 (s,1H), 6.67 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.24 (s, 1H),5.52 (dd, J = 5.9, 1.9 Hz, 1H), 4.95 (s, 1H), 4.35 (dd, J = 7.4, 5.0 Hz,1H), 3.61 (d, J = 8.4 Hz, 1H), 3.13-3.00 (m, 2H), 2.90-2.80 (m, 4H),2.74-2.59 (m, 2H), 2.50-2.40 (m, 1H), 2.27 (dd, J = 17.9, 6.1 Hz, 1H),2.05 (d, J = 17.9 Hz, 1H), 1.62 (d, J = 10.9 Hz, 1H), one protonobscured by solvent peaks B6

445 ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 9.16 (br s, 1H), 8.10 (d,J = 7.1 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H),6.24 (s, 1H), 5.57-5.49 (m, 2H), 4.96 (s, 1H), 4.41-4.31 (m, 1H),4.06-4.97 (m, 1H), 3.61 (d, J = 6.1 Hz, 1H), 3.36 (d, partially obscuredby solvent peak, 1H), 3.11-3.01 (m, 2H), 2.84 (apparent d, J = 3.9 Hz,3H), 2.69- 2.60 (m, 1H), 2.43 (dd, J = 13.1, 5.0 Hz, 1H), 2.27 (dd, J =18.0, 6.0 Hz, 1H), 2.05 (d, J = 18.0 Hz, 1H), 1.62 (d, J = 10.7 Hz, 1H),1.41 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H) B7

489 ¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (d, J = 6.8 Hz, 1H), 6.58 (d, J =8.1 Hz, 1H), 6.53 (d, J = 8.1 Hz, 1H), 5.51 (dd, J = 5.6, 2.5 Hz, 1H),4.83 (s, 1H), 4.37-4.27 (m, 1H), 4.22 (dd, J = 8.4, 4.3 Hz, 1H), 3.10(d, J = 18.9 Hz, 1H), 2.93 (d, J = 5.6 Hz, 1H), 2.64 (dd, J = 18.9, 5.9Hz, 1H), 2.48- 2.40 (m, 2H), 2.36 (s, 3H), 2.34-1.93 (m, 5H), 1.45-1.33(m, 4H), CO₂H and three OH protons not observed B8

436 ¹H NMR (300 MHz, DMSO-d₆) δ 9.34 (s, 1H), 9.14 (br s, 1H), 7.50-7.419 m, 2H), 7.40-7.30 9 m, 3H), 6.68 (d, J = 8.1 Hz, 1H), 6.61 (d, J = 8.1Hz, 1H), 6.25 (d, J = 5.4 Hz 1H), 6.21 (s, 1H), 5.32 (dd, J = 23.7, 3.9Hz, 1H), 4.97 (s, 1H), 3.60 (d, J = 6.0 Hz, 1H), 3.09-3.00 (m, 2H), 2.83(d, J = 4.2 Hz, 3H), 2.72-2.52 (m, 1H), 2.22 (dd, J = 18.3, 6.3 Hz, 1H),2.01 (d, J = 17.7 Hz, 1H), 1.62 (d, J = 11.1 Hz, 1H) B9

418 ¹H NMR (300 MHz, DMSO-d₆) δ 12.43 (br s, 1H), 9.30 (s, 1H), 9.16 (brs, 1H), 6.69-6.64 (m, 2H), 6.25 (s, 1H), 5.90 (s, 1H), 5.55 (s, 1H),4.93 (s, 1H), 4.49 (s, 1H), 3.62 (s, 1H), 3.18-3.00 (m, 2H), 2.83 (s,3H), 2.80-2.58 (m, 3H), 2.29-2.26 (m, 1H), 2.07 (d, J = 18.0 Hz, 1H),1.62 (d, J = 13.2 Hz, 1H), two protons obscured by solvent peaks B10

489 ¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (d, J = 7.3 Hz, 1H), 6.57 (d, J =8.1 Hz, 1H), 6.52 (d, J = 8.1 Hz, 1H), 5.51 (dd, J = 4.4, 2.8 Hz, 1H),4.83 (s, 1H), 4.43-4.32 (m, 1H), 4.27 (dd, J = 8.8, 3.7 Hz, 1H), 3.08(d, J = 18.6 Hz, 1H), 2.85 (d, J = 5.8 Hz, 1H), 2.65-2.54 (m, 2H),2.48-2.38 (m, 1H), 2.34 (s, 3H), 2.30-2.17 (m, 2H), 2.10 (d, J = 8.7 Hz,1H), 2.07-1.98 (m, 2H), 1.43-1.34 (m, 4H), CO₂H, CF₃CO₂H, and three OHprotons not observed B11

489 ¹H NMR (300 MHz, DMSO-d₆) δ 8.08 (t, J = 5.6 Hz, 1H), 6.58 (d, J =8.1 Hz, 1H), 6.53 (d, J = 8.1 Hz, 1H), 5.53 (dd, J = 5.5, 2.6 Hz, 1H),4.85 (s, 1H), 4.22 (dd, J = 8.1, 4.5 Hz, 1H), 3.41-3.24 (m, 2H), 3.12(d, J = 18.8 Hz, 1H), 2.95 (d, J = 6.0 Hz, 1H), 2.70-2.51 (m, 4H),2.49-4.22 (m, 1H), 2.40 (s, 3H), 2.35-1.95 (m, 5H), 1.41 (d, J = 12.2Hz, 1H), CO₂H and three OH protons not observed B12

515 ¹H NMR (300 MHz, DMSO-d₆) δ 6.58 (d, J = 8.1 Hz, 1H), 6.53 (d, J =8.1 Hz, 1H), 5.51 (dd, J = 5.5, 2.5 Hz, 1H), 4.86-4.83 (m, 1H), 4.39(dd, J = 8.7, 3.5 Hz, 1H), 4.29-4.24 (m, 1H), 3.65-3.54 (m, 2H), 3.10(d, J = 18.8 Hz, 1H), 2.93 (d, J = 5.9 Hz, 1H), 2.69-2.60 (m, 3H), 2.39(s, 3H), 2.30-2.20 (m, 2H), 2.15 (d, J = 13.4 Hz, 1H), 2.10-1.92 (m,5H), 1.40 (d, J = 11.1 Hz, 1H), five protons not observed B13

396 ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 9.15 (br s, 1H), 7.37-7.28(m, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.38-6.35(m, 2H), 6.24 (s, 1H), 5.98 (d, J = 15.0 Hz, 1H), 5.59-5.57 (m, 1H),5.03 (s, 1H), 3.63-3.61 (m, 1H), 3.41-3.33 (m, 1H), 3.09-3.05 (m, 2H),2.84 (d, J = 4.5 Hz, 3H), 2.67-2.60 (m, 1H), 2.49-2.41 (m, 1H),2.31-2.23 (m, 1H), 2.11-2.05 (m, 1H), 1.85 (d, J = 4.5 Hz, 3H),1.65-1.60 (m, 1H) B14

446 ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s, 1H), 9.15 (br s, 1H), 6.68 (d,J = 8.4 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.25 (br s, 1H), 5.59-5.55(m, 1H), 5.50 (d, J = 5.7 Hz, 1H), 5.15 (q, J = 6.9 Hz, 1H), 4.96 (s,1H), 4.29-4.20 (m, 1H), 3.62 (br s, 1H), 3.41-3.33 (m, 1H), 3.10-3.03(m, 2H), 2.83 (s, 3H), 2.68-2.56 (m, 1H), 2.46-2.41 (m, 1H), 2.33-2.25(m, 1H), 2.09- 2.03 (m, 1H), 1.64-1.60 (m, 1H), 1.53 (d, J = 6.9 Hz,3H), 1.32 (d, J = 6.6 Hz, 3H) B15

510 ¹H NMR (300 MHz, DMSO-d₆) δ 9.40 (br s, 1H), 9.18 (br s, 1H), 8.94(br s, 1H), 8.82 (d, J = 7.2 Hz, 1H), 7.73 (br s, 3H), 7.47 (s, 1H), 6.7(d, J = 8.1 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.27 (s, 1H), 5.53-5.51(m, 1H), 4.91 (s, 1H), 4.69 (q, J = 7.2 Hz, 1H), 3.63 (d, J = 4.8 Hz,1H), 3.39 (d, J = 19.8 Hz, 1H), 3.28-2.93 (m, 7H), 2.85 (s, 3H),2.74-2.55 (m, 1H), 2.29 (dd, J = 17.7, 6.0 Hz, 1H), 2.04 (d, J = 18.0Hz, 1H), three protons not observed B16

507 ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s, 1H), 9.17 (br s, 1H), 8.43 (d,J = 7.2 Hz, 1H), 7.47-7.10 (m, 5H), 6.65 (q, J = 8.1 Hz, 2H), 6.27-6.23(m, 2H), 5.48 (dd, J = 6.0, 2.1 Hz, 1H), 4.95 (d, J = 4.5 Hz, 1H), 4.91(s, 1H), 4.36 (m, 1H), 3.59 (m, 1H), 3.06-3.00 (m, 2H), 2.82 (s, 3H),2.72-2.38 (m, 3H), 2.28-2.20 (m, 1H), 2.06-2.00 (m, 1H), 1.63-1.60 (m,1H), 1.41 (d, J = 7.2 Hz, 3H) B17

507 ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.15 (s, 1H), 8.15 (t, J =5.8 Hz, 1H), 7.41-7.37 (m, 2H), 7.33- 7.23 (m, 3H), 6.65 (q, J = 7.9 Hz,2H), 6.22-6.20 (m, 2H), 5.46 (dd, J = 5.8, 1.9 Hz, 1H), 4.94 (s, 1H),4.90 (d, J = 4.5 Hz, 1H), 3.60 (s, 1H), 3.40-3.32 (m, 2H), 3.13-3.00 (m,2H), 2.83 (s, 3H), 2.62 (t, J = 7.0 Hz, 3H), 2.50-2.38 (m, 1H),2.28-2.19 (m, 1H), 2.03 (d, J = 18.0 Hz, 1H), 1.61 (d, J = 12.3 Hz, 1H)B18

459 ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 9.16 (s, 1H), 7.78 (s,3H), 6.66 (q, J = 10.5 Hz, 2H), 6.23 (s, 1H), 5.59 (dd, J = 6.0, 4.2 Hz,1H), 5.17 (q, J = 6.9 Hz, 1H), 3.62 (m, 1H), 3.08 (m, 4H), 2.63-2.84 (m,6H), 2.45-2.49 (m, 4H), 2.05 (d, J = 18.3 Hz, 1H), 1.61 (d, J = 12.3 Hz,1H), 1.54 (d, J = 6.9 Hz, 3H) B19

487 ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.13 (br s, 1H), 8.32 (brs, 3H), 6.66 (apparent q, J = 9.6 Hz, 2H), 6.21 (br s, 1H), 5.60 (dd, J= 6.0, 2.1 Hz, 1H), 5.34 (q, J = 7.2 Hz, 1H), 4.96 (s, 1H), 4.11 (t, J =6.6 Hz, 1H), 3.71-3.53 (m, 1H, partially obscured by water peak),3.07-3.04 (m, 2H), 2.83 (s, 3H), 2.63-2.41 (m, 3H), 2.33-2.25 (m, 1H),2.06 (d, J = 18.0 Hz, 1H), 1.91-1.57 (m, 4H), 1.58 (d, J = 7.2 Hz, 3H),0.93 (t, J = 6.3 Hz, 6H) B20

445 ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.15 (s, 1H), 7.84 (t, J =5.9 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.23(s, 1H), 5.56-5.51 (m, 2H), 4.96 (s, 1H), 4.00-3.91 (m, 1H), 3.61 (d, J= 5.4 Hz, 1H), 3.42-3.31 (m, 3H), 3.12- 3.00 (m, 2H), 2.83 (s, 3H), 2.62(t, J = 6.9 Hz, 3H), 2.50-2.39 (m, 1H), 2.26 (dd, J = 17.7, 6.0 Hz, 1H),2.06 (d, J = 17.7 Hz, 1H), 1.62 (d, J = 11.6 Hz, 1H), 1.20 (d, J 6.8 Hz,3H) B21

507 ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.13 (s, 1H), 7.79 (s,3H), 7.59-7.56 (m, 2H), 7.49-7.47 (m, 3H), 6.64 (q, J = 11.4 Hz, 2H),6.23 (s, 1H), 6.15 (s, 1H), 5.59 (dd, J = 6.0, 2.1 Hz, 1H), 4.87 (s,1H), 3.61 (m, 1H), 3.10 (m, 4H), 2.85-2.83 (m, 5H), 2.65-2.43 (m, 3H),2.29-2.21 (m, 1H), 2.06 (d, J = 18.3 Hz, 1H), 1.62-1.58 (m, 1H) B22

521 ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.15 (s, 1H), 8.35 (s,3H), 7.35-7.27 (m, 5H), 6.66 (apparent q, J = 9.6 Hz, 2H), 6.24 (s, 1H),5.59 (dd, J = 6.0, 2.1 Hz, 1H), 5.30 (q, J = 7.2 Hz, 1H), 4.97 (s, 1H),4.44 (t, J = 6.6 Hz, 1H), 3.62 (m, 1H), 3.25-3.05 (m, 5H), 2.84 (s, 3H),2.64 (m, 1H), 2.29-2.26 (m, 1H), 2.07 (d, J = 18.3 Hz, 1H), 1.64-1.61(m, 1H), 1.51 (d, J = 6.9 Hz, 3H), one proton obscured by solvent peaksB23

517 ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 9.15 (s, 1H), 7.79 (t, J =6.0 Hz, 1H), 6.65 (apparent q, J = 8.4 Hz, 1H), 6.25 (s, 1H), 5.58 (dd,J = 6.0, 2.1 Hz, 1H), 5.11 (q, J = 7.2 Hz, 1H), 4.96 (s, 1H), 3.94 (m,1H), 3.62 (m, 1H), 3.38 (m, 4H), 3.05 (m, 2H), 2.83 (s, 3H), 2.64 (m,1H), 2.57 (t, J = 6.9 Hz, 2H), 2.42 (m, 2H), 2.29 (m, 1H), 2.06 (d, J =18.0 Hz, 1H), 1.63 (d, J = 11.4 Hz, 1H), 1.52 (d, J = 9.6 Hz, 3H), 1.19(d, J = 9.6 Hz, 3H) B24

712 ¹H NMR (300 MHz, DMSO-d₆) δ 9.46 (broad s, 1.5H), 8.24-8.15 (m, 2H),7.41-7.20 (m, 10H), 6.72 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H),5.36 (dd, J = 6.3, 1.8 Hz, 1H), 5.03 (s, 1H), 4.92-4.90 (m, 2H), 4.68(d, J = 6.3 Hz, 1H), 3.46-3.10 (m, 8H), 3.00-2.71 (m, 5H), 2.69-2.51 (m,4H), 2.43-2.35 (m, 1H), 2.05 (d, J = 18.6 Hz, 1H), 1.76 (d, J = 12.6 Hz,1H) B25

489 ¹H NMR (300 MHz, DMSO-d₆) δ 8.33 (br s, 3H), 6.63 (apparent q, J =8.1 Hz, 2H), 5.58 (dd, J = 6.0, 2.1 Hz, 1H), 5.01 (q, J = 6.9 Hz, 1H),4.88 (s, 1H), 3.71 (m, 1H), 3.55 (m, 1H), 3.04-2.97 (m, 4H), 2.79-2.72(m, 4H), 2.63-2.40 (m, 2H), 2.28-2.22 (m, 1H), 2.04 (d, J = 18.3 Hz,1H), 1.60 (d, J = 12.6 Hz, 1H), 1.52 (d, J = 6.9 Hz, 3H), CO₂H and twoOH protons not observed B26

588 ¹H NMR (300 MHz, DMSO-d₆) δ 9.70-9.40 (m, 1.6H), 7.92-7.84 (m, 2H),6.73 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 5.50 (dd, J = 6.3,1.6 Hz, 1H), 5.06 (s, 1H), 4.73 (d, J = 5.7 Hz, 1H), 4.01-3.91 (m, 2H),3.45- 3.13 (m, 10H), 3.17-2.89 (m, 4H), 2.87-2.70 (m, 1H), 2.69-2.52 (m,4H), 2.47-2.3 (m, 1H), 2.09 (d, J = 18.6 Hz, 1H), 1.78 (d, J = 12.7 Hz,1H), 1.21 (d, J = 2.7 Hz, 3H), 1.19 (d, J = 2.7 Hz, 3H) B27

559 ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.14 (br s, 1H), 7.89 (d,J = 8.1 Hz, 1H), 6.66 (apparent q, J = 8.1 Hz, 1H), 6.23 (s, 1H), 5.58(dd, J = 6.0, 2.1 Hz, 1H), 5.53 (br s, 1H), 5.15 (q, J = 6.9 Hz, 1H),4.96 (s, 1H), 4.40 (m, 1H), 4.01 (m, 1H), 3.62 (m, 1H), 3.11-3.03 (m,2H), 2.84 (d, J = 4.5 Hz, 3H), 2.65 (m, 1H), 2.43 (m, 2H), 2.27 (m, 1H),2.06 (d, J = 17.7 Hz, 1H), 1.75-1.61 (m, 4H), 1.53 (d, J = 6.9 Hz, 3H),1.21 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 6.0 Hz, 3H), 0.86 (d, J = 5.7 Hz,3H), one proton obscured by solvent peaks B28

489 ¹H NMR (300 MHz, DMSO-d₆) δ 12.99 (br s, 1H), 9.29 (s, 1H), 9.16 (s,1H), 8.05 (q, J = 8.4 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.63 (d, J =8.2 Hz, 1H), 6.23 (s, 1H), 5.69 (br s, 1H), 5.52-5.49 (m, 1H), 4.94 (s,1H), 4.72-4.64 (m, 1H), 4.02 (q, J = 6.8 Hz, 1H), 3.61 (d, J = 6.1 Hz,1H), 3.13-3.00 (m, 3H), 3.00-2.87 (m, 2H), 2.87-2.78 (m, 3H), 2.78-2.55(m, 1H), 2.48-2.38 (m, 1H), 2.27 (dd, J = 17.8, 6.1 Hz, 1H), 2.05 (d, J= 17.8 Hz, 1H), 1.62 (d, J = 12.0 Hz, 1H), 1.22 (d, J = 6.8 Hz, 1H), twoprotons obscured by solvent peaks B29

490 ¹H NMR (300 MHz, DMSO-d₆) δ 6.57 (apparent q, J = 7.8 Hz, 2H), 5.56(dd, J = 5.7, 2.4 Hz, 1H), 5.10 (q, J = 6.9 Hz, 1H), 4.84 (s, 1H), 4.24(dd, J = 8.1, 4.2 Hz, 1H), 3.14 (d, J = 18.9 Hz, 1H), 3.01 (m, 1H), 2.79(dd, J = 15.6, 4.2 Hz, 1H), 2.75-2.54 (m, 3H), 2.44 (s, 3H), 2.33-2.13(m, 2H), 2.09-1.96 (m, 2H), 1.50 (d, J = 6.9 Hz, 3H), 1.42 (m, 1H),CO₂H, HCl, and OH protons not observed B30

508 ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.13 (s, 1H), 7.60-7.56(m, 2H), 7.49-7.46 (m, 3H), 6.64 (apparent q, J = 8.1 Hz, 2H), 6.24 (s,1H), 6.14 (s, 1H), 5.60-5.54 (m, 2H), 4.87 (s, 1H), 4.31 (m, 1H), 3.03(m, 1H), 2.82 (m, 3H), 2.64-2.39 (m, 3H), 2.30-2.22 (m, 1H), 2.05 (d, J= 18.0 Hz, 1H), 1.59 (d, J = 11.4 Hz, 3H), 1.38 (d, J = 6.9 Hz, 3H) B31

702 ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 9.13 (s, 1H), 7.58-7.55(m, 2H), 7.47-7.44 (m, 3H), 6.63 (q, J = 8.1 Hz, 2H), 6.23 (s, 1H), 6.09(s, 1H), 5.58 (dd, J = 6.3, 2.1 Hz, 1H), 4.86 (s, 1H), 3.06 (m, 1H),2.82 (d, J = 4.8 Hz, 3H), 2.64-2.22 (m, 6H), 2.05 (m, 1H), 2.58 (m, 3H),1.23 (m, 30H), 0.85 (t, J = 6.9 Hz, 3H) B32

676 ¹H NMR (300 MHz, DMSO-d₆) δ 12.97 (br s, 1H), 9.40 (br s, 2H), 8.10(d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H),6.66 (d, J = 8.2 Hz, 1H), 5.42 (dd, J = 6.1, 1.7 Hz, 1H), 5.01 (s, 1H),4.76- 4.60 (m, 3H), 4.06-3.98 (m, 2H), 2.30-3.10 (m, 4H), 3.09-2.56 (m,10H), 2.48-2.33 (m, 2H), 2.11 (d, J = 19.0 Hz, 1H), 1.78 (d, J = 12.8Hz, 1H), 1.21 (d, J = 6.8 Hz, 6H) B33

508 ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s, 1H), 9.14 (s, 1H), 7.46-7.43(m, 2H), 7.38-7.27 (m, 3H), 6.64 (apparent q, J = 8.1 Hz, 2H), 6.21 (s,1H), 6.16 (d, J = 5.7 Hz, 1H), 5.49 (dd, J = 5.7, 2.1 Hz, 1H), 5.24-5.15(m, 2H), 4.82 (s, 1H), 3.06 (m, 1H), 2.83 (d, J = 4.2 Hz, 3H), 2.63-2.22(m, 6H), 2.03 (d, J = 18.0 Hz, 1H), 1.60 (d, J = 10.2 Hz, 1H), 1.50 (d,J = 6.9 Hz, 3H) B34

474 ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (br s, 1H), 6.66 (d, J = 8.2 Hz,1H), 6.60 (d, J = 8.2 Hz, 1H), 5.57 (dd, J = 5.8, 2.0 Hz, 1H), 5.11 (q,J = 7.0 Hz, 1H), 4.92 (s, 1H), 3.02-2.78 (m, 2H), 2.8-2.58 (m, 5H),2.50-2.31 (m, 1H), 2.24 (dd, J = 17.8, 5.4 Hz, 1H), 2.04 (d, J = 19.9Hz, 1H), 1.57 (d, J = 11.3 Hz, 1H), 1.51 (d, J = 7.0 Hz, 3H), CO₂H andOH protons not observed, five protons obscured by solvent peaks B35

536 ¹H NMR (300 MHz, DMSO-d₆) δ 7.59-7.51 (m, 2H), 7.50-7.40 (m, 3H),6.57 (d, J = 8.1 Hz, 1H), 6.51 (d, J = 8.1 Hz, 1H), 6.07 (s, 1H), 5.55(dd, J = 5.5, 2.6 Hz, 1H), 4.70 (s, 1H), 3.20-3.03 (m, 2H), 3.84 (d, J =6.0 Hz, 1H), 2.74-2.63 (m, 2H), 2.62- 2.54 (m, 3H), 2.43 (dd, J = 10.9,3.6 Hz, 1H), 2.32 (s, 3H), 2.19 (dd, J = 12.3, 4.5 Hz, 1H), 2.13-1.93(m, 3H), 1.36 (d, J = 10.8 Hz, 1H), CO₂H and OH protons not observed B36

534 ¹H NMR (300 MHz, DMSO-d₆) δ 9.44 (br s, 1H), 9.31 (br s, 1H), 9.15(br s, 1H), 6.75-6.58 (m, 3H), 5.46-5.41 (m, 2H), 5.02 (s, 1H), 4.69 (d,J = 5.9 Hz, 1H), 4.25-4.33 (m, 3H), 3.60- 2.60 (m, 11H), 2.47-2.37 (m,1H), 2.10 (d, J = 19.3 Hz, 1H), 1.77 (d, J = 11.4 Hz, 1H) B37

552 ¹H NMR (300 MHz, DMSO-d₆) δ 7.59-7.54 (m, 2H), 7.48-7.44 (m, 3H),6.55 (apparent q, J = 7.8 Hz, 2H), 6.08 (s, 1H), 5.56 (dd, J = 5.7, 2.4Hz, 1H), 4.74 (s, 1H), 4.26 (dd, J = 8.4, 4.2 Hz, 1H), 3.15 (s, 1H),3.09 (s, 1H), 2.97 (d, J = 5.7 Hz, 1H), 2.88 (dd, J = 15.9, 4.2 Hz, 1H),2.73-1.95 (m, 6H), 2.41 (s, 3H), 1.40 (d, J = 11.1 Hz, 1H), CO₂H, HCl,and three OH protons not observed B38

640 ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.13 (s, 1H), 6.65(apparent q, J = 8.1 Hz, 2H), 6.23 (s, 1H), 5.57 (dd, J = 6.3, 2.1 Hz,1H), 5.09 (q, J = 6.9 Hz, 1H), 4.95 (s, 1H), 3.09 (m, 1H), 2.84 (d, J =3.9 Hz, 3H), 2.63- 2.26 (m, 5H), 2.05 (d, J = 18.0 Hz, 1H), 1.64-1.49(m, 7H), 1.23 (m, 30H), 0.85 (t, J = 6.6 Hz, 3H) B39

700 ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 9.12 (s, 1H), 7.58-7.54(m, 2H), 7.48-7.45 (m, 3H), 6.64 (q, J = 8.1 Hz, 2H), 6.23 (s, 1H), 6.09(s, 1H), 5.58 (dd, J = 6.3, 2.1 Hz, 1H), 5.32 (t, J = 4.8 Hz, 2H), 4.86(s, 1H), 3.04 (m, 1H), 2.82 (d, J = 4.8 Hz, 3H), 2.64-2.22 (m, 3H),2.08-1.96 (m, 5H), 1.60-1.40 (m, 4H), 1.23 (m, 24H), 0.85 (t, J = 6.9Hz, 3H) B40

490 ¹H NMR (300 MHz, DMSO-d₆) δ 12.39 (br s, 1H), 9.30 (s, 1H), 9.17 (s,1H), 6.69 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.28 (s, 1H),5.84 (br s, 1H), 5.5-9 (dd, J = 5.9, 2.0 Hz, 1H), 5.17 (q, J = 7.0 Hz,1H), 4.97 (s, 1H), 4.47 (dd, J = 8.6, 4.0 Hz, 1H), 3.63 (d, J = 6.2 Hz,1H), 3.13-3.00 (m, 2H), 2.84 (d, J =3.3 Hz, 3H), 2.72 (dd, J = 16.0, 4.2Hz, 1H), 2.69-2.57 (m, 1H), 2.50-2.40 (m, 1H), 2.29 (dd, J = 18.0, 6.0Hz, 1H), 2.06 (d, J = 18.0 Hz, 1H), 1.62 (d, J = 11.2 Hz, 1H), 1.53 (d,J = 7.0 Hz, 3H), two protons obscured by sovent peaks B41

712 ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.13 (s, 1H), 6.65(apparent q, J = 8.1 Hz, 2H), 6.23 (s, 1H), 5.58 (dd, J = 6.3, 2.1 Hz,1H), 5.23 (q, J = 6.9 Hz, 1H), 5.08 (q, J = 7.2 Hz, 1H), 4.95 (s, 1H),3.06 (m, 1H), 2.83 (d, J = 4.8 Hz, 3H), 2.63-2.25 (m, 5H), 2.06 (d, J =17.4 Hz, 1H), 1.64-1.46 (m, 10H), 1.23 (m, 30H), 0.85 (t, J = 6.9 Hz,3H) B42

638 ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.14 (s, 1H), 6.65(apparent q, J = 8.1 Hz, 2H), 6.23 (s, 1H), 5.57 (dd, J = 5.7, 2.1 Hz,1H), 5.32 (t, J = 4.5 Hz, 2H), 5.09 (q, J = 7.2 Hz, 1H), 4.95 (s, 1H),3.09 (m, 1H), 2.83 (d, J = 4.5 Hz, 3H), 2.67-2.24 (m, 7H), 2.09-1.95 (m,5H), 1.64-1.49 (m, 6H), 1.25 (m, 21H), 0.85 (t, J = 6.3 Hz, 3H) B43a

508 ¹H NMR (300 MHz, DMSO-d₆) δ 12.23 (br s, 1H), 9.30 (s, 1H), 9.15 (s,1H), 7.97 (t, J = 6.0 Hz, 1H), 6.64 (apparent q, J = 8.1 Hz, 2H), 6.22(s, 1H), 5.85 (s, 1H), 5.55 (dd, J = 6.0, 2.1 Hz, 1H), 4.96 (s, 1H),4.22 (dd, J = 8.7, 3.6 Hz, 1H), 3.62-3.43 (m, 5H), 3.11-3.02 (m, 1H),2.84 (d, J = 4.8 Hz, 3H), 2.66-2.60 (m, 4H), 2.49-2.23 (m, 3H), 2.05 (d,J = 17.7 Hz, 1H), 1.62 (d, J = 10.5 Hz, 1H) B43b

471 ¹H NMR (300 MHz, DMSO-d₆) δ 12.86 (br s, 1H), 9.30 (s, 1H), 9.15 (s,1H), 8.65 (t, J = 5.5 Hz, 1H), 6.92 (d, J = 15.5 Hz, 1H), 6.68 (d, J =8.1 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.53 (d, J = 15.5 Hz, 1H), 6.21(s, 1H), 5.55 (dd, J = 6.0, 2.0 Hz, 1H), 4.96 (s, 1H), 3.61 (d, J = 6.3Hz, 1H), 3.50-3.42 (m, 2H), 3.13-3.01 (m, 3H), 2.84 (d, J = 4.7 Hz, 3H),2.70-2.62 (m, 3H), 2.50-2.40 (m, 1H), 2.32-2.22 (m, 1H), 2.06 (d, J =17.5 Hz, 1H), 1.62 (d, J = 11.3 Hz, 1H) B44

680 ¹H NMR (300 MHz, DMSO-d₆) δ 12.75 (br s, 1H), 9.26 (s, 1H), 9.13 (s,1H), 6.64 (apparent q, J = 8.1 Hz, 2H), 6.23 (s, 1H), 5.59 (dd, J = 6.0,2.1 Hz, 1H), 5.40 (dd, J = 7.8, 4.2 Hz, 1H), 5.32 (t, J = 4.5 Hz, 2H),4.93 (s, 1H), 3.62-3.41 (m, 1H), 3.04-2.88 (m, 4H), 2.84 (d, J = 4.5 Hz,3H), 2.66-2.24 (m, 6H), 2.09-1.97 (m, 4H), 1.64-1.52 (m, 3H), 1.25 (m,23H), 0.85 (t, J = 6.9 Hz, 3H) B45

682 ¹H NMR (300 MHz, DMSO-d₆) δ 12.77 (s, 1H), 9.26 (s, 1H), 9.14 (s,1H), 6.65 (q, J = 8.1 Hz, 2H), 6.24 (s, 1H), 5.59 (dd, J = 6.0, 2.1 Hz,1H), 5.40 (dd, J = 7.8, 4.2 Hz, 1H), 4.92 (s, 1H), 3.04-2.83 (m, 6H),2.63-2.24 (m, 6H), 2.06 (d, J = 18.0 Hz, 1H), 1.64-1.52 (m, 1H), 1.25(m, 31H), 0.85 (t, J = 6.9 Hz, 3H) B46

416 ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 9.14 (s, 1H), 6.65 (q, J =8.1 Hz, 2H), 6.25 (s, 1H), 5.58 (dd, J = 6.0, 2.1 Hz, 1H), 5.08 (q, J =6.9 Hz, 1H), 4.95 (s, 1H), 3.05 (m, 1H), 2.83 (d, J = 4.2 Hz, 3H),2.67-2.24 (m, 6H), 2.11-2.03 (m, 4H), 1.62 (d, J = 12.6 Hz, 1H), 1.51(d, J = 7.2 Hz, 3H) B47

488 ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.14 (s, 1H), 6.65 (q, J =8.1 Hz, 2H), 6.24 (s, 1H), 5.58 (dd, J = 5.7, 1.8 Hz, 1H), 5.23 (q, J =6.9 Hz, 1H), 5.07 (q, J = 7.2 Hz, 1H), 4.95 (s, 1H), 3.05 (m, 1H), 2.82(s, 3H), 2.63- 2.24 (m, 6H), 2.08-2.03 (m, 4H), 1.62 (d, J = 12.3 Hz,1H), 1.54 (d, J = 7.2 Hz, 3H), 1 .47 (d, J = 7.2 Hz, 3H) B48

550 ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 9.12 (s, 1H), 7.60-7.55(m, 2H), 7.52-7.46 (m, 3H), 6.65 (q, J = 8.1 Hz, 2H), 6.24 (s, 1H), 6.21(s, 1H), 5.58 (dd, J = 6.0, 2.1 Hz, 1H), 5.15 (q, J = 6.9 Hz, 1H), 4.86(s, 1H), 3.03 (m, 1H), 2.82 (s, 3H), 2.63-2.22 (m, 6H), 2.08-2.02 (m,4H), 1.62 (d, J = 13.5 Hz, 1H), 1.54 (d, J = 7.2 Hz, 3H) B49

530 ¹H NMR (300 MHz, DMSO-d₆) δ 12.82 (s, 1H), 9.27 (s, 1H), 9.15 (s,1H), 6.65 (apparent q, J = 8.1 Hz, 2H), 6.25 (s, 1H), 5.59 (dd, J = 6.0,2.1 Hz, 1H), 5.50 (t, J = 5.4 Hz, 1H), 5.08 (q, J = 7.2 Hz, 1H), 4.91(s, 1H), 3.04 (m, 1H), 2.95 (d, J = 6.0 Hz, 2H), 2.84 (d, J = 4.5 Hz,3H), 2.67- 2.25 (m, 8H), 2.08-2.03 (m, 4H), 1.62 (d, J = 11.7 Hz, 1H),1.46 (d, J = 6.9 Hz, 3H) B50

710 ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.14 (s, 1H), 6.65(apparent q, J = 8.1 Hz, 2H), 6.23 (s, 1H), 5.57 (dd, J = 6.3, 2.1 Hz,1H), 5.32 (t, J = 4.5 Hz, 1H), 5.22 (q, J = 6.9 Hz, 1H), 5.08 (q, J =7.2 Hz, 1H), 4.95 (s, 1H), 3.06 (m, 1H), 2.84 (d, J = 4.5 Hz, 3H),2.63-2.25 (m, 8H), 2.09-1.95 (m, 4H), 1.64-1.46 (m, 10H), 1.23 (m, 21H),0.85 (t, J = 6.6 Hz, 3H) B51

536 ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.15 (br s, 1H), 7.50-7.44(m, 2H), 7.44-7.40 (m, 3H), 6.68 (d, J = 8.2 Hz, 1H), 6.62 (d, J = 8.2Hz, 1H), 6.22 (s, 1H), 5.85 (s, 1H), 5.49 (dd, J = 6.0, 1.9 Hz, 1H),4.93 (s, 1H), 3.61 (d, J = 6.3 Hz, 1H), 3.12-3.01 (m, 2H), 2.84 (s, 3H),2.79-2.70 (m, 4H), 2.70-2.58 (m, 1H), 2.42 (dd, J = 13.3, 4.7 Hz, 1H),2.25 (dd, J = 17.1, 7.1 Hz, 1H), 2.04 (d, J = 17.1 Hz, 1H), 1.61 (d, J =11.2 Hz, 1H), CO₂H proton not observed, one proton obscured by solventpeaks B52

478 ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s, 1H), 9.15 (br s, 1H), 7.60-7.51(m, 2H), 7.51-7.43 (m, 3H), 6.68 (d, J = 8.1 Hz, 1H), 6.61 (d, J = 8.1Hz, 1H), 6.27 (s, 1H), 6.08 (s, 1H), 5.58 (dd, J = 6.0, 1.9 Hz, 1H),4.87 (s, 1H), 3.61 (d, J = 6.1 Hz, 1H), 3.11-3.00 (m, 2H), 2.83 (d, J =4.6 Hz, 3H), 2.70- 2.55 (m, 1H), 2.42 (dd, J = 12.8, 4.2 Hz, 1H), 2.26(dd, J = 18.0, 6.1 Hz, 1H), 2.17 (s, 3H), 2.05 (d, J = 18.0 Hz, 1H),1.60 (d, J = 11.1 Hz, 1H), one proton obscured by solvent peaks B53

676 ¹H NMR (300 MHz, DMSO-d₆) δ 9.55 (br s, 2H), 8.03-7.97 (m, 2H), 6.73(d, J = 8.2 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 5.50 (dd, J = 6.7, 1.8Hz, 1H), 5.06 (s, 1H), 4.73 (d, J = 6.0 Hz, 1H), 4.26-4.21 (m, 2H),3.45-3.13 (m, 10H), 3.08-2.90 (m, 4H), 2.86- 2.70 (m, 1H), 2.70-2.53 (m,5H), 2.45-2.25 (m, 3H), 2.09 (d, J = 18.6 Hz, 1H), 1.78 (d, J = 13.5 Hz,1H), CO₂H protons not observed B54

518 ¹H NMR (300 MHz, DMSO-d₆) δ 12.3 (s, 1H), 12.6 (s, 1H), 9.30 (s,1H), 9.14 (s, 1H), 6.65 (apparent q, J = 8.1 Hz, 2H), 6.22 (s, 1H), 5.53(dd, J = 6.3, 2.1 Hz, 1H), 5.23 (dd, J = 7.8, 4.5 Hz, 1H), 4.95 (s, 1H),3.06 (m, 1H), 2.91-2.66 (m, 11H), 2.47 (m, 3H), 2.27 (m, 1H), 2.06 (d, J= 18.0 Hz, 1H), 1.63 (d, J = 11.7 Hz, 1H) B55

460 ¹H NMR (300 MHz, DMSO-d₆) δ 13.4 (br s, 1H), 9.29 (s, 1H), 9.14 (brs, 1H), 6.65 (apparent q, J = 8.1 Hz, 2H), 6.24 (s, 1H), 5.55 (dd, J =5.7, 2.1 Hz, 1H), 5.28 (dd, J = 8.4, 4.5 Hz, 1H), 4.96 (s, 1H),3.12-2.94 (m, 4H), 2.84 (d, J = 3.6 Hz, 3H), 2.67-2.42 (m, 4H), 2.27(dd, J = 17.7, 6.0 Hz, 1H), 2.09-2.03 (m, 4H), 1.63 (d, J = 11.7 Hz, 1H)B56

550 ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (br s, 1H), 9.16 (br s, 1H),7.53-7.49 (m, 2H), 7.42-7.39 (m, 3H), 6.68 (d, J = 8.2 Hz, 1H), 6.63 (d,J = 8.2 Hz, 1H), 6.25 (s, 1H), 6.06 (s, 1H), 5.46 (dd, J = 5.9, 2.0 Hz,1H), 5.26 (q, J = 7.1 Hz, 1H), 4.79 (s, 1H), 6.61 (d, J = 6.1 Hz, 1H),3.36 (d, J = 20.0 Hz, 1H), 3.12-3.01 (m, 2H), 2.87-2.82 (m, 3H),2.69-2.57 (m, 1H), 2.41 (dd, J = 13.2, 4.7 Hz, 1H), 2.26 (dd, J = 18.0,6.2 Hz, 1H), 2.13 (s, 3H), 2.03 (d, J = 18.0 Hz, 1H), 1.59 (d, J = 10.9Hz, 1H), 1.50 (q, J = 7.1 Hz, 3H) B57

474 ¹H NMR (300 MHz, DMSO-d₆) δ 13.05 (br s, 1H), 9.33 (br s, 1H), 9.18(br s, 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.28 (s,1H), 5.52 (dd, J = 5.7, 1.8 Hz, 1H), 4.98- 4.89 (m, 2H), 3.63 (d, J =6.2 Hz, 1H), 3.37 (d, J = 19.9 Hz, 1H), 3.13- 3.00 (m, 2H), 3.84 (s,3H), 2.76-2.55 (m, 5H), 2.43 (dd, J = 13.2, 4.6 Hz, 1H), 2.27 (dd, J =17.9, 6.1 Hz, 1H), 2.05 (d, J = 16.2 Hz, 1H), 1.62 (d, J = 11.0 Hz, 1H),1.40 (d, J = 7.1 Hz, 3H) B58

531 ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (br s, 1H), 9.16 (br s, 1H), 8.45(d, J = 8.3 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H),6.24 (s, 1H), 5.52 (dd, J = 5.9, 1.9 Hz, 1H), 4.98 (q, J = 6.8 Hz, 1H),4.93 (s, 1H), 4.65 (q, J = 6.9 Hz, 1H), 3.61 (d, J = 6.3 Hz, 1H),3.11-2.93 (m, 3H), 2.91- 2.74 (m, 4H), 2.70-2.58 (m, 1H), 2.48-2.39 (m,1H), 2.28 (dd, J = 17.7, 6.2 Hz, 1H), 2.06 (d, J = 14.0 Hz, 1H), 1.62(d, J = 11.0 Hz, 1H), 1.33 (d, J = 6.9 Hz, 3H), CO₂H proton notobserved, four protons obscured by solvent peaks B59

800 ¹H NMR (300 MHz, DMSO-d₆, Mixture of diastereomers) δ 9.35 (s, 1H),8.48 (d, J = 8.4 Hz, 0.18H), 8.43 (d, J = 8.3 Hz, 0.82H), 8.25 (d, J =7.2 Hz, 1H), 7.44-7.17 (m, 10H), 6.69 (d, J = 8.2 Hz, 1H), 6.63 (d, J =8.2 Hz, 1H), 6.41-6.30 (m, 2H), 5.34 (d, J = 5.9 Hz, 0.18H), 5.25 (d, J= 4.5 Hz, 0.82H), 5.00-4.89 (m, 3H), 4.74-4.47 (m, 3H), 3.18-2.94 (m,4H), 2.93-2.67 (m, 8H), 2.45-2.43 (m, 2H), 2.09-1.98 (m, 1H), 1.73- 1.61(m, 1H), CO₂H protons not observed B60

518 ¹H NMR (300 MHz, DMSO-d₆) δ 13.2 (br s, 1H), 12.6 (br s, 1H), 9.30(s, 1H), 9.17 (br s, 1H), 6.64 (q, J = 8.1 Hz, 2H), 6.24 (br s, 1H),5.53 (dd, J = 6.3, 2.1 Hz, 1H), 5.22 (dd, J = 7.8, 4.5 Hz, 1H), 4.95 (s,1H), 3.41-3.32 (m, 1H), 3.04 (m, 1H), 2.86-2.61 (m, 10H), 2.51-2.42 (m,3H), 2.26 (m, 1H), 2.06 (d, J = 16.0 Hz, 1H), 1.62 (d, J = 10.8 Hz, 1H)B61a

551 ¹H NMR (300 MHz, DMSO-d₆) δ 13.01 (br s, 1H), 9.30 (br s, 1H), 9.15(br s, 1H), 6.37 (d, J = 8.3 Hz, 1H), 7.46-7.18 (m, 5H), 6.68 (d, J =8.1 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.38 (br s, 1H), 6.21 (s, 1H),5.35 (d, J = 4.2 Hz, 1H), 4.96 (s, 1H), 4.89 (s, 1H), 4.67 (q, J = 6.3Hz, 1H), 3.64- 3.58 (m, 1H), 3.18-2.79 (m, 8H), 2.77-2.60 (m, 2H),2.30-2.18 (dd, J = 17.6, 6.1 Hz, 1H), 2.03 (d, J = 18.32 Hz, 1H), 1.62(d, J = 12.2 Hz, 1H) B61b

607 ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (br s, 1H), 9.14 (br s, 1H), 8.41(d, J = 8.1 Hz, 1H), 7.43-7.38 (m, 2H), 7.34-7.24 (m, 3H), 6.68 (d, J =8.1 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.32 (br s, 1H), 6.22 (s, 1H),5.41- 5.39 (m, 1H), 4.96 (s, 1H), 4.90 (s, 1H), 4.61-4.52 (m, 1H),3.63-3.59 (m, 1H), 3.12-2.95 (m, 3H), 2.88- 2.78 (m, 4H), 2.70-2.59 (m,1H), 2.45-2.40 (m, 1H), 2.25 (dd, J = 17.5, 6.3 Hz, 1H), 2.04 (d, J =18.6 Hz, 1H), 1.62 (d, J = 11.6 Hz, 1H), 1.33 (s, 9H), one protonobscured by solvent peaks B62

532 ¹H NMR (300 MHz, DMSO-d₆) δ 6.55 (apparent q, J = 8.1 Hz, 2H), 5.56(dd, J = 5.7, 2.4 Hz, 1H), 5.35 (dd, J = 9.0, 3.6 Hz, 1H), 5.23 (q, J =8.1 Hz, 1H), 3.09 (d, J = 18.6 Hz, 1H), 2.94-2.72 (m, 3H), 2.60 (dd, J =18.6, 6.3 Hz, 1H), 2.51-2.44 (m, 4H), 2.35 (s, 3H), 2.27 (m, 1H),2.13-2.00 (m, 6H), 1.53 (d, J = 6.9 Hz, 3H), 1.39 (d, J = 10.8 Hz, 1H),CO₂H proton not observed B63

418 ¹H NMR (300 MHz, DMSO-d₆) δ 12.7 (s, 1H), 9.31 (s, 1H), 9.15 (br s,1H), 6.65 (apparent q, J = 7.8 Hz, 2H), 6.22 (s, 1H), 5.64 (s, 1H), 5.52(dd, J = 6.0, 2.1 Hz, 1H), 4.95 (s, 1H), 4.35 (m, 1H), 3.41-3.33 (m,2H), 3.03 (m, 1H), 2.89 (d, J = 4.5 Hz, 1H), 2.83 (s, 3H), 2.72-2.61 (m,1H), 2.44-2.42 (m, 1H), 2.27 (m, 1H), 2.06 (d, J = 17.7 Hz, 3H), 1.63(d, J = 10.8 Hz, 1H) B64

503 ¹H NMR (300 MHz, DMSO-d₆) δ 12.3 (br s, 1H), 9.32 (br s, 1H), 9.16(br s, 1H), 8.44 (br s, 3H), 6.66 (apparent q, J = 8.1 Hz, 2H), 6.25 (s,1H), 5.61 (dd, J = 6.0, 2.1 Hz, 1H), 5.34 (q, J = 7.2 Hz, 1H), 4.99 (s,1H), 4.23 (m, 1H), 3.62 (m, 3H), 3.08 (m, 1H), 2.84 (s, 3H), 2.63-2.26(m, 4H), 2.11-2.05 (m, 3H), 1.76 (m, 1H), 1.63-1.58 (m, 4H) B65

688 ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.14 (br s, 1H), 6.65(apparent q, J = 8.1 Hz, 2H), 6.23 (s, 1H), 5.62 (dd, J = 6.0, 2.4 Hz,1H), 5.52 (dd, J = 7.2, 4.5 Hz, 1H), 5.36 (dd, J = 8.7, 3.9 Hz, 1H),4.92 (s, 1H), 3.62-3.31 (m, 1H), 3.11-3.01 (m, 2H), 2.97-2.63 (m, 8H),2.47-2.27 (m, 2H), 2.08-2.03 (m, 4H), 1.63 (m, 1H), 1.44 (s, 9H), 1.39(s, 9H), one proton obscured by solvent peaks B66

518 ¹H NMR (300 MHz, DMSO-d₆) δ 9.34 (s, 1H), 9.15 (br s, 1H), 6.68 (d,J = 8.1 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.29 (br s, 1H), 5.77 (d, J =2.8 Hz, 1H), 5.68 (d, J = 2.8 Hz, 1H), 5.52 (d, J = 4.1 Hz, 1H), 4.83(s, 1H), 3.62 (d, J = 6.0 Hz, 1H), 3.12-3.01 (m, 3H), 2.83 (s, 3H),2.70-2.56 (m, 1H), 2.46-2.39 (m, 1H), 2.28 (dd, J = 17.7, 6.0 Hz, 1H),2.19 (s, 3H), 2.15 (s, 3H), 2.07 (d, J = 16.4 Hz, 1H), 1.62 (d, J = 11.2Hz, 1H), CO₂H proton not observed B67

594 ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.15 (s, 1H), 7.51-7.39(m, 5H), 6.68 (d, J = 8.1 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.27 (s,1H), 5.92- 5.87 (m, 1H), 5.61-5.47 (m, 2H), 4.94 (m, 0.7H), 4.90 (s,0.3H), 3.62 (d, J = 6.4 Hz, 1H), 3.24-3.01 (m, 5H), 2.83 (s, 3H),2.71-2.56 (m, 1H), 2.48-2.36 (m, 1H), 2.33-2.21 (m, 1H), 2.12- 2.02 (m,4H), 1.66-1.57 (m, 1H), CO₂H proton not observed B68

490 ¹H NMR (300 MHz, DMSO-d₆) δ 13.1 (br s, 1H), 9.30 (s, 1H), 9.14 (brs, 1H), 6.64 (apparent q, J = 8.1 Hz, 2H), 6.22 (s, 1H), 5.96 (d, J =6.3 Hz, 1H), 5.55 (dd, J = 6.0, 1.8 Hz, 1H), 5.03-4.97 (m, 2H), 4.52 (m,1H), 3.41-3.33 (m, 1H), 3.04 (m, 1H), 2.95 (dd, J = 15.9, 4.2 Hz, 1H),2.84 (s, 3H), 2.73-2.64 (m, 2H), 2.51-2.42 (m, 3H), 2.27 (m, 1H), 2.05(d, J = 17.7 Hz, 1H), 1.63 (m, 1H), 1.42 (d, J = 6.9 Hz, 3H) B69

594 ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (br s, 1H), 9.15 (br s, 1H),7.52-7.39 (m, 5H), 6.68 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H),6.23 (s, 1H), 5.97 (s, 1H), 5.57-5.47 (m, 2H), 4.96 (s, 1H), 6.31 (d, J= 6.0 Hz, 1H), 3.12-3.00 (m, 4H), 2.84 (s, 3H), 2.71-2.49 (m, 1H),2.50-2.40 (m, 1H), 2.34-2.21 (m, 1H), 2.15-2.00 (m, 4H), 1.63 (d, J =11.8 Hz, 1H), CO₂H proton not observed B70

532 ¹H NMR (300 MHz, DMSO-d₆) δ 13.3 (br s, 1H), 9.29 (s, 1H), 9.15 (brs, 1H), 6.65 (apparent q, J = 8.1 Hz, 2H), 6.24 (s, 1H), 5.58 (dd, J =5.7, 2.1 Hz, 1H), 5.27 (dd, J = 8.4, 4.5 Hz, 1H), 5.18 (q, J = 6.9 Hz,1H), 4.97 (s, 1H), 3.11-2.96 (m, 4H), 2.83 (d, J = 3.9 Hz, 3H),2.73-2.41 (m, 4H), 2.29 (m, 1H), 2.09-2.04 (m, 4H), 1.63 (m, 1H), 1.52(d, J = 7.2 Hz, 3H) B71

460 ¹H NMR (300 MHz, DMSO-d₆) δ 12.8 (br s, 1H), 9.29 (s, 1H), 9.16 (brs, 1H), 6.65 (apparent q, J = 8.1 Hz, 2H), 6.26 (s, 1H), 5.60 (dd, J =5.7, 2.1 Hz, 1H), 5.39 (dd, J = 7.2, 4.2 Hz, 1H), 4.92 (s, 1H),3.62-3.34 (m, 1H), 3.11-2.83 (m, 7H), 2.73-2.39 (m, 3H), 2.29 (m, 1H),2.11 (s, 3H), 2.06 (m, 1H), 1.62 (m, 1H) B72

594 ¹H NMR (300 MHz, DMSO-d₆) δ 12.8 (br s, 1H), 9.34 (s, 1H), 9.27 (brs, 1H), 7.60-7.54 (m, 2H), 7.49-7.45 (m, 3H), 6.68 (d, J = 8.1 Hz, 1H),6.66 (d, J = 8.1 Hz, 1H), 6.24 (s, 2H), 5.58 (dd, J = 5.7, 2.1 Hz, 1H),5.44 (dd, J = 9.0, 3.6 Hz, 1H), 4.86 (s, 1H), 3.40-3.33 (m, 2H),3.07-2.99 (m, 2H), 2.89-2.82 (m, 4H), 2.63-2.39 (m, 4H), 2.25 (m, 1H),2.09-2.02 (m, 3H), 1.59 (m, 1H) B73

652 ¹H NMR (300 MHz, DMSO-d₆) δ 9.35 (s, 1H), 9.15 (br s, 1H), 7.46-7.40(m, 5H), 6.68 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.30 (s,1H), 6.01 (s, 1H), 5.96 (d, J = 2.7 Hz, 1H), 5.86 (d, J = 2.7 Hz, 1H),5.56-5.51 (m, 1H), 4.83 (s, 1H), 3.62 (d, J = 6.2 Hz, 1H), 3.11-3.01 (m,1H), 3.83 (s, 3H), 2.70-2.54 (m, 1H), 2.49-2.39 (m, 1H), 2.32-2.16 (m,5H), 2.07 (d, J = 18.0 Hz, 1H), 2.01 (s, 3H), 1.62 (d, J = 12.0 Hz, 1H),CO₂H proton not observed B74

503 ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (br s, 1H), 9.16 (br s, 1H), 8.27(br s, 3H), 6.66 (apparent q, J = 8.1 Hz, 2H), 6.26 (s, 1H), 5.58 (dd, J= 6.0, 2.1 Hz, 1H), 5.13 (q, J = 4.2 Hz, 1H), 4.96 (s, 1H), 3.96 (m,1H), 3.44 (m, 2H), 3.05 (m, 1H), 2.84 (s, 3H), 2.73- 2.41 (m, 5H), 2.28(m, 1H), 2.18-2.00 (m, 3H), 1.62 (m, 1H), 1.53 (d, J = 7.2 Hz, 3H), CO₂Hproton not observed B75

532 ¹H NMR (300 MHz, DMSO-d₆) δ 13.2 (br s, 1H), 9.29 (s, 1H), 9.15 (brs, 1H), 6.65 (apparent q, J = 8.1 Hz, 2H), 6.23 (s, 1H), 5.58 (dd, J =6.3, 2.1 Hz, 1H), 5.42 (dd, J = 9.3, 3.6 Hz, 1H), 5.09-4.97 (m, 2H),3.43-3.33 (m, 1H), 3.18 (dd, J = 17.1, 3.6 Hz, 1H), 3.11-2.93 (m, 3H),2.84 (s, 3H), 2.73-2.42 (m, 3H), 2.28 (m, 1H), 2.13-2.04 (m, 4H), 1.63(m, 1H), 1.43 (d, J = 7.2 Hz, 3H) B76

652 ¹H NMR (300 MHz, DMSO-d₆) δ 13.51 (br s, 1H), 9.33 (s, 1H), 9.15 (brs, 1H), 7.51-7.40 (m, 5H), 6.67 (d, J = 8.2 Hz, 1H), 6.62 (d, J = 8.2Hz, 1H), 6.30 (s, 1H), 6.03 (d, J = 2.7 Hz, 1H), 5.98-5.94 (m, 2H),5.56- 5.53 (m, 1H), 4.83 (s, 1H), 3.62 (d, J = 6.0 Hz, 1H), 3.40-3.33(m, 1H), 3.12-3.02 (m, 2H), 3.83 (apparent d, J = 3.5 Hz, 3H), 2.67-2.56(m, 1H), 2.47-2.38 (m, 1H), 2.31-2.21 (m, 4H), 2.11 (s, 3H), 2.08 (d, J= 17.7 Hz, 1H), 1.63 (d, J = 11.1 Hz, 1H) B77

434 ¹H NMR (300 MHz, CD₃OD) δ 6.65- 6.57 (m, 2H), 5.55 (dd, J = 5.4, 2.8Hz, 1H), 4.99 (s, 1H), 4.65 (d, J = 2.2 Hz, 1H), 4.53 (d, J = 2.2 Hz,1H), 3.56 (d, J = 6.5 Hz, 1H), 3.35 (d, J = 20.0 Hz, 1H), 3.13-3.03 (m,2H), 2.83 (s, 3H), 2.82-2.74 (m, 1H), 2.57 (dt, J = 13.4, 4.9 Hz, 1H),2.25-2.17 (m, 2H), 1.71 (dd, J = 13.5, 3.0 Hz, 1H), CO₂H, CF₃CO₂H, andfour OH protons not observed B78

518 ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (br s, 1H), 9.16 (br s, 1H), 6.87(d, J = 8.2 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.30 (s, 1H), 5.82 (d, J= 2.9 Hz, 1H), 5.60 (dd, J = 6.0, 1.9 Hz, 1H), 5.56 (d, J = 2.9 Hz, 1H),4.94 (s, 1H), 3.63 (d, J = 6.0 Hz, 1H), 3.42-3.30 (m, 1H), 3.11-3.02 (m,2H), 2.84 (apparent d, J = 3.8 Hz, 3H), 2.70- 2.56 (m, 1H), 2.48-2.39(m, 1H), 2.28 (d, J = 18.0, 6.1 Hz, 1H), 2.18 (s, 3H), 2.15 (s, 3H),2.11-2.02 (m, 1H), 1.63 (d, J = 11.3 Hz, 1H), CO₂H proton not observedB79

634 ¹H NMR (300 MHz, DMSO-d₆) δ 9.35 (s, 1H), 9.15 (br s, 1H), 6.64(apparent q, J = 8.1 Hz, 2H), 6.27 (br s, 1H), 5.85 (d, J = 2.7 Hz, 1H),5.77 (d, J = 2.7 Hz, 1H), 5.53 (dd, J = 5.7, 1.8 Hz, 1H), 5.29 (dd, J =8.4, 3.9 Hz, 1H), 4.83 (s, 1H), 3.32 (m, 1H), 3.03 (m, 1H), 2.90-2.63(m, 6H), 2.51- 2.41 (m, 3H), 2.27 (m, 1H), 2.21 (s, 3H), 2.13 (s, 3H),2.04 (m, 1H), 1.62 (m, 1H), CO₂H protons not observed B80

546 ¹H NMR (300 MHz, DMSO-d₆) δ 12.30 (br s, 1H), 9.30 (br s, 1H), 9.17(br s, 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.27 (s,1H), 5.60 (dd, J = 6.0, 1.9 Hz, 1H), 5.45 (t, J = 5.9 Hz, 1H), 4.93 (s,1H), 4.14 (q, J = 7.1 Hz, 2H), 3.62 (d, J = 6.0 Hz, 1H), 3.14-2.98 (m,4H), 2.84 (apparent d, J = 4.7 Hz, 3H), 2.70- 2.57 (m, 3H), 2.43 (dd, J= 13.3, 4.5 Hz, 1H), 2.28 (dd, J = 17.9, 6.0 Hz, 1H), 2.05 (d, J = 17.9Hz, 1H), 1.63 (d, J = 11.1 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H), threeprotons obscured by solvent peaks B81

590 ¹H NMR (300 MHz, DMSO-d₆) δ 9.37 (br s, 1H), 9.17 (br s, 1H), 6.68(d, J = 8.2 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.33 (br s, 1H), 5.89 (d,J = 2.7 Hz, 1H), 5.85 (d, J = 2.7 Hz, 1H), 5.55- 5.53 (m, 1H), 5.05 (q,J = 7.0 Hz, 1H), 4.84 (s, 1H), 3.63 (d, J = 6.2 Hz, 1H), 3.11-3.03 (m,2H), 3.83 (apparent d, J = 1.8 Hz, 3H), 2.71- 2.57 (m, 1H), 2.47-2.39(m, 1H), 2.43 (dd, J = 18.0, 6.3 Hz, 1H), 2.22 (s, 3H), 2.15 (s, 3H),2.07 (d, J = 18.0 Hz, 1H), 1.6-2 (d, J = 11.2 Hz, 1H), 1.39 (d, J = 7.0Hz, 3H), CO₂H proton not observed B82

590 ¹H NMR (300 MHz, DMSO-d₆) δ 13.9 (br s, 1H), 9.29 (br s, 1H), 9.17(br s 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.26 (s,1H), 5.72 (d, J = 2.8 Hz, 1H), 5.62 (d, J = 2.8 Hz, 1H), 5.59 (dd, J =6.0, 2.2 Hz, 1H), 5.28 (q, J = 7.0 Hz, 1H), 5.00 (s, 1H), 3.62 (d, J =6.3 Hz, 1H), 3.37 (d, J = 20.0 Hz, 1H), 3.13-3.01 (m, 2H), 2.83(apparent d, J = 4.6 Hz, 3H), 2.70-2.57 (m, 1H), 2.43 (dd, J = 14.5, 4.7Hz, 1H), 2.29 (dd, J = 17.9, 6.4 Hz, 1H), 2.14 (s, 3H), 2.11-2.02 (m,4H), 1.63 (d, J = 10.8 Hz, 1H), 1.50 (d, J = 7.0 Hz, 3H) B83

489 ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (br s, 2H), 8.44 (br s, 2H), 6.66(apparent q, J = 8.1 Hz, 2H), 6.26 (s, 2H), 5.59 (m, 1H), 5.33 (q, J =7.2 Hz, 1H), 4.98 (s, 1H), 4.45 (m, 1H), 3.35 (m, 2H), 3.11-2.88 (m,4H), 2.84 (s, 3H), 2.73-2.42 (m, 3H), 2.29 (m, 1H), 2.06 (m, 1H),1.64-1.53 (m, 4H) B84

676 ¹H NMR (300 MHz, DMSO-d₆) δ 12.5 (br s, 2H), 9.51-9.28 (m, 2H), 8.13(t, J = 5.7 Hz, 1H), 8.02 (t, J = 5.5 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H),6.66 (d, J = 8.2 Hz, 1H), 5.50 (dd, J = 6.6, 1.7 Hz, 1H), 5.06 (s, 1H),4.78-4.65 (m, 1H), 4.32-4.27 (m, 2H), 3.56-3.43 (m, 2H), 3.40-3.15 (m,6H), 3.08- 2.88 (m, 4H), 2.87-2.69 (m, 2H), 2.67-2.57 (m, 3H), 2.48-2.30(m, 4H), 2.08 (d, J = 18.8 Hz, 1H), 1.8 (d, J = 12.9 Hz, 1H), twoprotons obscured by solvent peaks B85

594 ¹H NMR (300 MHz, DMSO-d₆) δ 13.4 (br s, 1H), 9.28 (s, 1H), 9.14 (brs, 1H), 7.59-7.54 (m, 2H), 7.52-7.45 (m, 3H), 6.64 (apparent q, J = 8.1Hz, 2H), 6.25 (s, 1H), 6.17 (s, 1H), 5.60 (dd, J = 5.7, 2.1 Hz, 1H),5.31 (dd, J = 8.7, 3.9 Hz, 1H), 4.87 (s, 1H), 3.62- 3.33 (m, 2H),3.14-2.96 (m, 4H), 2.82 (d, J = 4.2 Hz, 3H), 2.64-2.38 (m, 2H), 2.25 (m,1H), 2.09-2.02 (m, 4H), 1.60 (m, 1H) B86

634 ¹H NMR (300 MHz, DMSO-d₆) δ 13.5 (br s, 1H), 12.8 (br s, 1H), 9.36(s, 1H), 9.16 (br s, 1H), 6.65 (apparent q, J = 8.1 Hz, 2H), 6.28 (br s,1H), 5.82 (d, J = 2.4 Hz, 1H), 5.78 (d, J = 2.4 Hz, 1H), 5.54 (dd, J =6.0, 1.8 Hz, 1H), 5.35 (dd, J = 7.5, 3.9 Hz, 1H), 4.84 (s, 1H),3.62-3.34 (m, 2H), 3.02 (m, 1H), 2.93-2.72 (m, 5H), 2.63- 2.40 (m, 3H),2.27 (m, 1H), 2.22 (s, 3H), 2.11 (s, 3H), 2.07 (m, 1H), 1.62 (m, 1H) B87

615 ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.16 (br s, 1H), 8.05-7.98(m, 2H), 7.64 (br s, 3H), 6.65 (apparent q, J = 8.1 Hz, 2H), 6.25 (s,2H), 5.58 (dd, J = 5.7, 1.8 Hz, 1H), 5.10 (q, J = 7.2 Hz, 1H), 4.96 (s,1H), 4.15 (m, 1H), 3.67-3.27 (m, 4H), 3.11-3.03 (m, 2H), 2.84 (d, J =4.8 Hz, 3H), 2.78-2.72 (m, 2H), 2.67-2.46 (m, 2H), 2.29 (m, 1H), 2.06(m, 1H), 1.84 (s, 3H), 1.65-1.25 (m, 11H) B88

506 ¹H NMR (300 MHz, DMSO-d₆) δ 12.83 (br s, 1H), 9.30 (br s, 1H), 9.17(br s, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.27 (s,1H), 5.60 (dd, J = 6.0. 2.0 Hz, 1H), 5.18 (q, J = 7.0 Hz, 1H), 4.99 (s,1H), 4.48 (d, J = 2.2 Hz, 1H), 4.39 (d, J = 2.1 Hz, 1H), 3.63 (d, J =6.3 Hz, 1H), 3.38 (d, J = 20.0 Hz, 1H), 3.14-3.00 (m, 2H), 2.84(apparent d, J = 4.2 Hz, 3H), 2.70-2.57 (m, 1H), 2.44 (dd, J = 13.6, 4.9Hz, 1H), 2.29 (dd, J = 17.9, 6.1 Hz, 1H), 2.07 (d, J = 17.9 Hz, 1H),1.63 (d, J = 11.3 Hz, 1H), 1.53 (d, J = 7.0 Hz, 3H), two protonsobscured by solvent peaks B89

490 ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.14 (br s, 1H), 6.64(apparent q, J = 8.4 Hz, 2H), 6.24 (br s, 1H), 5.97 (d, J = 6.0 Hz, 1H),5.57 (d, J = 3.9 Hz, 1H), 5.00-4.93 (m, 2H), 4.53 (m, 1H), 3.41-3.33 (m,2H), 3.05 (m, 1H), 2.89-2.72 (m, 6H), 2.63-2.41 (m, 3H), 2.27 (m, 1H),2.07 (m, 1H), 1.62 (m, 1H), 1.40 (d, J = 7.2 Hz, 3H) B90

558 ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.16 (br s, 1H), 8.62 (t,J = 5.4 Hz, 1H), 8.09 (br s, 3H), 6.65 (apparent q, J = 8.1 Hz, 2H),6.24 (s, 1H), 5.58 (dd, J = 6.0, 2.1 Hz, 1H), 5.12 (q, J = 6.9 Hz, 1H),4.96 (s, 1H), 3.67-3.27 (m, 4H), 3.05 (m, 1H), 2.84 (d, J = 4.8 Hz, 3H),2.63-2.41 (m, 6H), 2.28 (m, 1H), 2.05 (m, 1H), 1.64-1.52 (m, 7H), 0.89(dd, J = 6.0, 2.1 Hz, 6H) B91

615 ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.16 (br s, 1H), 8.43 (d,J = 6.3 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.61 (br s, 3H), 6.65(apparent q, J = 8.1 Hz, 2H), 6.22 (s, 1H), 5.57 (dd, J = 6.0, 2.1 Hz,1H), 5.14 (q, J = 6.9 Hz, 1H), 4.35-4.30 (m, 3H), 3.46- 3.33 (m, 2H),3.11 (m, 1H), 2.84 (d, J = 5.1 Hz, 3H), 2.74-2.41 (m, 3H), 2.27 (m, 1H),2.07 (m, 1H), 1.84 (s, 3H), 1.64-1.32 (m, 14H) B92

568 ¹H NMR (300 MHz, DMSO-d₆) δ 12.86 (br s, 1H), 9.30 (br s, 1H), 9.14(br s, 1H), 7.62-7.56 (m, 2H), 7.50- 7.43 (d, 3H), 6.68 (d, J = 8.1 Hz,1H), 6.62 (d, J = 8.1 Hz, 1H), 6.27 (s, 1H), 6.16 (s, 1H), 5.61 (dd, J =6.0, 2.0 Hz, 1H), 4.90 (s, 1H), 4.58 (d, J = 2.0 Hz, 1H), 4.38 (d, J =2.3 Hz, 1H), 3.61 (d, J = 6.2 Hz, 1H), 3.37 (d, J = 19.8 Hz, 1H),3.13-3.00 (m, 2H), 2.83 (d, J = 4.3 Hz, 3H), 2.68-2.56 (m, 1H), 2.41(dd, J = 13.0, 4.7 Hz, 1H), 2.26 (dd, J = 18.0, 6.2 Hz, 1H), 2.07 (d, J= 18.0 Hz, 1H), 1.60 (d, J = 10.8 Hz, 1H), two protons obscured bysolvent peaks B93

506 ¹H NMR (300 MHz, DMSO-d₆) δ 13.4 (br s, 1H), 9.32 (s, 1H), 9.17 (brs, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.26 (s,1H), 5.83 (br s, 2H), 5.56 (dd, J = 5.9, 1.9 Hz, 1H), 5.03 (s, 1H), 4.99(q, J = 7.1 Hz, 1H), 4.62 (s, 1H), 4.56 (s, 1H), 3.62 (d, J = 6.1 Hz,1H), 3.38 (d, J = 20.0 Hz, 1H), 3.13-3.01 (m, 2H), 2.84 (apparent d, J =4.1 Hz, 3H), 2.71- 2.58 (m, 1H), 2.45 (dd, J = 14.1, 5.6 Hz, 1H), 2.30(dd, J = 18.0, 6.1 Hz, 1H), 2.06 (d, J = 18.0 Hz, 1H), 1.64 (d, J = 10.7Hz, 1H), 1.43 (d, J = 7.1 Hz, 3H) B94

542 ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.19 (br s, 2H), 8.61 (t,J = 5.7 Hz, 1H), 8.54 (br s, 1H), 6.66 (apparent q, J = 8.1 Hz, 2H),6.25 (s, 1H), 5.58 (dd, J = 6.0, 2.1 Hz, 1H), 5.12 (q, J = 6.9 Hz, 1H),4.96 (s, 1H), 4.13-3.03 (m, 10H), 2.84 (d, J = 4.5 Hz, 3H), 2.64-2.19(m, 5H), 2.05 (m, 1H), 1.92-1.77 (m, 3H), 1.62 (m, 1H) 1.53 (d, J = 7.2Hz, 3H) B95a

568 ¹H NMR (300 MHz, DMSO-d₆) δ 13.38 (br s, 1H), 9.32 (s, 1H), 9.17 (brs, 1H), 7.54-7.47 (m, 2H), 7.47- 7.39 (m, 3H), 6.69 (d, J = 8.2 Hz, 1H),6.63 (d, J = 8.2 Hz, 1H), 6.26 (s, 1H), 5.99-5.80 (m, 3H), 5.54 (dd, J =6.1, 2.0 Hz, 1H), 5.02 (s, 1H), 4.67 (d, J = 1.6 Hz, 1H), 4.59 (d, J =1.5 Hz, 1H), 3.62 (d, J = 7.1 Hz, 1H), 3.38 (d, J = 18.7 Hz, 1H),3.13-3.00 (m, 2H), 2.84 (s, 3H), 2.70-2.57 (m, 1H), 2.43 (dd, J = 14.2,5.5 Hz, 1H), 2.28 (dd, J = 17.5, 6.2 Hz, 1H), 2.05 (d, J = 17.7 Hz, 1H),1.63 (d, J = 10.5 Hz, 1H) B95b

568 ¹H NMR (300 MHz, DMSO-d₆) δ 13.28 (br s, 1H), 9.32 (s, 1H), 9.15 (brs, 1H), 7.56-7.47 (m, 2H), 7.47- 7.37 (m, 3H), 6.68 (d, J = 8.2 Hz, 1H),6.63 (d, J = 8.2 Hz, 1H), 6.29 (br s, 1H), 5.94-5.89 (m, 3H), 5.56-5.35(m, 1H), 5.03 (s, 1H), 4.70 (s, 1H), 4.64 (dd, J = 8.0, 2.4 Hz, 1H),3.61 (d, J = 5.6 Hz, 1H), 3.41-3.38 (m, 1H), 3.14-2.99 (m, 2H), 2.83 (s,3H), 2.71-2.58 (m, 1H), 2.47-2.38 (m, 1H), 2.27 (dd, J = 17.4, 6.5 Hz,1H), 205 (d, J = 18.0 Hz, 1H), 1.63 (d, J = 12.8 Hz, 1H) B96

558 ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 9.15 (br s, 1H), 8.93 (d,J = 6.9 Hz, 1H), 8.13 (br s, 3H), 6.65 (apparent q, J = 8.1 Hz, 2H),6.24 (s, 1H), 5.58 (dd, J = 6.0, 2.1 Hz, 1H), 5.19 (q, J = 6.9 Hz, 1H),4.95 (s, 1H), 4.47 (m, 1H), 3.75 (m, 1H), 3.64-3.52 (m, 2H), 3.05 (m,1H), 2.84 (d, J = 4.5 Hz, 3H), 2.73-2.41 (m, 3H), 2.27 (m, 1H), 2.07 (m,1H), 1.73-1.51 (m, 7H), 1.41 (d, J = 7.5 Hz, 3H), 0.91 (t, J = 6.6 Hz,6H) B97

574 ¹H NMR (300 MHz, DMSO-d₆) δ 12.35 (br s, 1H), 9.32 (s, 1H), 9.17 (brs, 1H), 8.61 (t, J = 5.4 Hz, 1H), 8.14 (br s, 3H), 6.66 (apparent q, J =8.1 Hz, 2H), 6.26 (s, 1H), 5.58 (dd, J = 6.0, 2.1 Hz, 1H), 5.11 (q, J =7.2 Hz, 1H), 4.96 (s, 1H), 3.74 (m, 1H), 3.67-3.27 (m, 4H), 3.06 (m,1H), 2.84 (s, 3H), 2.63-2.41 (m, 5H), 2.32-2.26 (m, 3H), 2.05 (m, 1H),1.96-1.88 (m, 2H), 1.62 (m, 1H), 1.53 (d, J = 7.2 Hz, 3H) B98

542 ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 9.25 (br s, 1H), 9.17 (brs, 1H), 8.97 (d, J = 6.6 Hz, 1H), 8.56 (brs, 1H), 6.66 (apparent q, J =8.1 Hz, 2H), 6.25 (s, 1H), 5.58 (dd, J = 6.0, 2.4 Hz, 1H), 5.18 (q, J =6.9 Hz, 1H), 4.95 (s, 1H), 4.44 (m, 1H), 4.21 (m, 1H), 3.67-3.03 (m,4H), 2.84 (d, J = 4.5 Hz, 3H), 2.72-2.41 (m, 3H), 2.31-2.27 (m, 2H),2.07 (m, 1H), 1.91-1.84 (m, 3H), 1.62 (m, 1H), 1.54 (d, J = 7.2 Hz, 3H),1.41 (d, J = 7.2 Hz, 3H) B99

592 ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 9.16 (br s, 1H), 8.49 (t,J = 5.4 Hz, 1H), 8.19 (br s, 3H), 7.37- 7.24 (m, 5H), 6.65 (apparent q,J = 8.1 Hz, 2H), 6.25 (s, 1H), 5.57 (dd, J = 5.7, 1.8 Hz, 1H), 5.08 (q,J = 6.9 Hz, 1H), 3.94 (m, 1H), 3.64-3.16 (m, 6H), 3.11-2.92 (m, 4H),2.84 (d, J = 3.3 Hz, 3H), 2.73-2.24 (m, 3H), 2.28 (m, 1H), 2.05 (m, 1H),1.61 (m, 1H), 1.53 (d, J = 7.2 Hz, 3H)

In further embodiments, the abuse-resistant opioid compound may beselected from one or more of:

Ex, No. Structure Name C1

(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7- yl2-(((S)-2-((S)-2-acetamido-4- methylpentanamido)propanoyl)oxy)propanoate C2

(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7- yl2-(((S)-2-((S)-2-amino-4- methylpentanamido)propanoyl)oxy) propanoate C3

(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7- yl2-(((S)-2-((S)-2-amino-3- phenylpropanamido)propanoyl)oxy) propanoate C4

(S)-2-amino-5-(((S)-1-(((S)-1- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl- 2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yl)amino)-5- oxopentanoic acid C5

(2R,3R)-2,3-diacetoxy-4-((S)-2- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-1-4,12-methanobenzofuro[3,2- e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoic acid C6

(S)-(S)-1-(((S)-1-(((4R,4aS,7aR,12bS)- 4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1- oxopropan-2-yl 2-acetamido-6-aminohexanoate C7

(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzaluro[3,2-e]isoquinolin-7- yl2-(((S)-2-((S)-2- acetamidopropanamido)propanoyl)oxy) propanoate C8

(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7- yl2-(((S)-2-((S)-2-acetamido-2- phenylacetamido)propanoyl)oxy) propanoateC9

(S)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl- 2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetic acid C10

(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7- yl2-((3-((S)-2-acetamido-4- methylpentanamido)propanoyl)oxy) propanoateC11

(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7- yl2-((3-((S)-2-acetoxy-2- phenylacetamido)propanoyl)oxy) propanoate C12

(S)-2-(((2R,3R)-2,3-dihydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoic acid C13

(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7- yl2-((3-((S)-2- acetoxypropanamido)propanoyl)oxy) propanoate C14

(R)-2-(((2R,3R)-2,3-dihydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)succinicacid C15

(S)-2-((S)-2-(((2R,3R)-2,3-dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy) propanamido)propanoic acid C16

(S)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin- 7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetic acid C17

(S)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin- 7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetic acid C18

(S)-2-(((2R,3R)-2,3-dihydroxy-4- (4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetic acid C19

(S)-2-(((2R,3R)-2,3-dihydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin- 7-yl)oxy)-4-oxobutanoyl)oxy)succinic acid C20

(2R,3R)-4-((S)-1-carboxy-3- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin- 7-yl)oxy)-3-oxopropoxy)-2,3-dihydroxy-4-oxobutanoic acid C21

(S)-2-(((S)-2-(((S)-2-acetamido-6- aminohexanoyl)oxy)propanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoic acid C22

(S)-2-(((S)-2-((S)-2-acetamido-6- aminohexanamido)propanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoic acid C23

(S)-2-((3-((S)-2-acetamido-6- aminohexanamido)propanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoic acid C24

(S)-2-(((S)-2-((4-(((4R,4aS,7aR,12bS)- 4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)propanoic acid C25

(S)-2-(((S)-2-((4-(((4R,4aS,7aR,12bS)- 4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4- oxobutanoyl)oxy)propanoyl)oxy)-2- phenylacetic acid C26

(S)-2-(((S)-2-((4-(((4R,4aS,7aR,12bS)- 4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)succinic acid C27

(R)-2-(((S)-2-((4-(((4R,4aS,7aR,12bS)- 4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)succinic acid C28

(S)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)- 4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2- phenylacetoxy)propanoic acid C29

(S)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)- 4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2- phenylacetoxy)-2-phenylacetic acid C30

(S)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)- 4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2- phenylacetoxy)succinic acid C31

(R)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)- 4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2- phenylacetoxy)succinic acid C32

(S)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)- 4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy) propanamido)propanoic acid C33

(S)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)- 4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4- oxobutanoyl)oxy)propanamido)-4- methylpentanoic acid C34

(S)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)- 4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy) propanamido)succinic acid C35

(R)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)- 4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy) propanamido)succinic acid C36

(S)-2-(((S)-4-(((4R,4aS,7aR,12bS)- 4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-(((S)-2- hydroxypropanoyl)oxy)-4- oxobutanoyl)oxy)propanoicacid C37

(S)-2-(((S)-2-((-aminopropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy) propanoic acid C38

(S)-2-(((S)-4-(((4R,4aS7aR,12bS)-4a- hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-((3-((S)-2- hydroxypropanamido)propanoyl)oxy)-4-oxobutanoyl)oxy)propanoic acid C39

(2R,3R)-4-(((S)-1-((S)-1- carboxyethoxy)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl- 2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)oxy)-2,3- dihydroxy-4-oxobutanoic acid C40

(S)-4-(((S)-1-((S)-1-carboxyethoxy)-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)oxy)-2- hydroxy-4-oxobutanoic acid C41

(S)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin- 7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid C42

(S)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl- 2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin- 7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid C43

(R)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin- 7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid C44

(R)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)succinicacid C45

(S)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)succinicacid C46

(R)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)succinicacid C47

(S)-2-(((S)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)propanoic acid C48

(S)-2-(((S)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)propanoic acid C49

(S)-2-(((S)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)-2-phenylacetic acid C50

(S)-2-(((S)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)-2-phenylacetic acid C51

(S)-2-(((S)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)succinic acid C52

(S)-2-(((S)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)succinic acid C53

(R)-2-(((S)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)succinic acid C54

(R)-2-(((S)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)succinic acid C55

(S)-2-(((S)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)propanoic acid C56

(S)-2-(((S)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)-2-phenylacetic acid C57

(S)-2-(((S)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)succinic acid C58

(R)-2-(((S)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)succinic acid C59

(S)-2-((S)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)propanoic acid C60

(S)-2-((S)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)propanoic acid C61

(S)-2-((S)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)-2-phenylacetic acid C62

(S)-2-((S)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)-2-phenylacetic acid C63

(S)-2-(((S)-2-(((S)-4- ((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-2-(((S)-2-hydroxypropanoyl)oxy)-4- oxobutanoyl)oxy)propanoyl)oxy) propanoic acidC64

(S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a- hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinoiin-7-yl)oxy)-2-(((S)-2- hydroxypropanoyl)oxy)-4- oxobutanoyl)oxy)succinicacid C65

(R)-2-(((S)-4-(((41R,4aS,7aR,12bS)-4a- hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-(((S)-2- hydroxypropanoyl)oxy)-4- oxobutanoyl)oxy)succinicacid C66

(S)-2-(((S)-2-(((S)-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-2-(((S)-2-hydroxypropanoyl)oxy)-4- oxobutanoyl)oxy)propanoyl)oxy) succinic acidC67

(R)-2-(((S)-2-(((S)-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-2-(((S)-2-hydroxypropanoyl)oxy)-4- oxobutanoyl)oxy)propanoyl)oxy) succinic acidC68

(S)-4-(S)-1-(((S)-1-((S)-1- carboxyethoxy)-1-oxopropan-2-yl)oxy)-4-(((4R,4aS,7aR,12bS)-4a- hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)oxy)-2- hydroxy-4-oxobutanoic acid C69

(S)-2-(((S)-2-(((S)-3-carboxy-3- hydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinic acid C70

(R)-2-(((S)-2-(((S)-3-carboxy-3- hydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinic acid C71

(S)-2-(((S)-2-(((S)-2-(((S)-3-carboxy-3- hydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)succinic acid C72

(R)-2-(((S)-2-(((S)-2-(((S)-3-carboxy-3- hydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)succinic acid C73

(2R,3R)-4-(((S)-1-(((S)-1-((S)-1- carboxyethoxy)-1-oxopropan-2-yl)oxy)-4-(((4R,4aS,7aR,12bS)-4a- hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)oxy)-2,3- dihydroxy-4-oxobutanoic acid C74

(S)-2-(((S)-2-(((2R,3R)-3-carboxy-2,3- dihydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinic acid C75

(R)-2-(((S)-2-(((2R,3R)-3-carboxy-2,3- dihydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinic acid C76

(S)-2-(((S)-2-(((S)-2-(((2R,3R)-3- carboxy-2,3-dihydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)succinic acid C77

(R)-2-(((S)-2-(((S)-2-(((2R,3R)-3- carboxy-2,3-dihydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)succinic acid C78

(S)-2-((S)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)succinic acid C79

(S)-2-((S)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)succinic acid C80

(R)-2-((S)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)succinic acid C81

(R)-2-((S)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)succinic acid C82

(S)-2-((S)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)propanoic acid C83

(S)-2-((S)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)-2-phenylacetic acid C84

(S)-2-((S)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)succinic acid C85

(R)-2-((S)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)succinic acid C86

(S)-2-((S)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)propanamido)propanoic acid C87

(S)-2-((S)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)propanamido)propanoic acid C88

(S)-2-((S)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)propanamido)-4-methylpentanoic acid C89

(S)-2-((S)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)propanamido)-4-methylpentanoic acid C90

(S)-2-((S)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)propanamido)succinic acid C91

(S)-2-((S)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)propanamido)succinic acid C92

(R)-2-((S)-2-(((S)-2-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)propanamido)succinic acid C93

(R)-2-((S)-2-(((S)-2-acetoxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)propanamido)succinic acid C94

(S)-2-((S)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)propanamido)propanoic acid C95

(S)-2-((S)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)propanamido)-4-methylpentanoic acid C96

(S)-2-((S)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)propanamido)succinic acid C97

(R)-2-((S)-2-(((S)-3-hydroxy-4- (((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a- hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7- yl)oxy)-4-oxobutanoyl)oxy)propanamido)succinic acid C98

(S)-2-(((S)-2-(((2R,3R)-2,3-dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)propanoic acid C99

(S)-2-(((S)-2-(((2R,3R)-2,3-dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)-2-phenylacetic acid C100

(S)-2-(((S)-2-(((2R,3R)-2,3-dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)succinic acid C101

(R)-2-(((S)-2-(((2R,3R)-2,3-dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl) oxy)succinic acid C102

(S)-2-((S)-2-(((2R,3R)-2,3-dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2- phenylacetoxy)propanoic acid C103

(S)-2-((S)-2-(((2R,3R)-2,3-dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2- phenylacetoxy)-2-phenylacetic acid C104

(S)-2-((S)-2-(((2R,3R)-2,3-dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2- phenylacetoxy)succinic acid C105

(R)-2-((S)-2-(((2R,3R)-2,3-dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2- phenylacetoxy)succinic acid C106

(S)-2-((S)-2-(((2R,3R)-2,3-dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy) propanamido)propanoic acid C107

(S)-2-((S)-2-(((2R,3R)-2,3-dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy) propanamido)-4-methylpentanoic acid C108

(S)-2-((S)-2-(((2R,3R)-2,3-dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy) propanamido)succinic acid C109

(R)-2-((S)-2-(((2R,3R)-2,3-dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9- methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy) propanamido)succinic acid

In further embodiments, the abuse-resistant opioid compound may beselected from one or more of:

Ex, No. Structure Name D1

(S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)succinic acid D2

(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)- 2-amino-3- phenylpropanamido)propanoyl)oxy)propanoate D3

(S)-2-amino-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5- oxopentanoic acid D4

(S)-(S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yl 2-acetamido-6- aminohexanoate D5

(2R,3R)-2,3-diacetoxy-4-((S)-2-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoic acid D6

(S)-4-amino-5-(((S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yl)amino)-5- oxopentanoic acid D7

(S)-2-amino-5-(((S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yl)amino)-5- oxopentanoic acid D8

(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2- acetamido-4- methylpentanamido)propanoyl)oxy)propanoate D9

(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)- 2-acetamido-4-methylpentanamido)propanoyl)oxy)propanoate D10

(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)- 2-acetoxy-2- phenylacetamido)propanoyl)oxy)propanoateD11

(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)- 2-acetoxypropanamido)propanoyl)oxy)propanoate D12

(R)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)succinic acid D13

(S)-2-((S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)propanamido)propanoic acid D14

(2R,3R)-4-((S)-1-carboxy-3-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropoxy)-2,3-dihydroxy-4-oxobutanoic acid D15

(R)-2-(((S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl)oxy)succinic acid D16

(R)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)succinic acid D17

(S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)-2-phenylacetic acid D18

(S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)-2-phenylacetic acid D19

(S)-2-(((S)-2-(((S)-2-acetamido-6- aminohexanoyl)oxy)propanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4- oxobutanoic acid D20

(S)-2-(((S)-2-((S)-2-acetamido-6- aminohexanamido)propanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4- oxobutanoic acid D21

(S)-2-((3-((S)-2-acetamido-6- aminohexanamido)propanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4- oxobutanoic acid D22

(S)-2-(((S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl)oxy)propanoic acid D23

(S)-2-(((S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl)oxy)-2-phenylacetic acid D24

(S)-2-(((S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl)oxy)succinic acid D25

(S)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)propanoic acid D26

(S)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)-2-phenylacetic acid D27

(S)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)succinic acid D28

(R)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)succinic acid D29

(S)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanamido)propanoic acid D30

(S)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanamido)-4-methylpentanoic acid D31

(S)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanamido)succinic acid D32

(R)-2-((S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanamido)succinic acid D33

(S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-(((S)-2-hydroxypropanoyl)oxy)-4-oxobutanoyl)oxy)propanoic acid D34

(S)-2-(((S)-2-((3-aminopropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoic acid D35

(S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-((3-((S)-2-hydroxypropanamido)propanoyl)oxy)-4- oxobutanoyl)oxy)propanoicacid D36

(2R,3R)-4-(((S)-1-((S)-1-carboxyethoxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)oxy)-2,3-dihydroxy-4-oxobutanoic acid D37

(S)-4-(((S)-1-((S)-1-carboxyethoxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)oxy)-2-hydroxy-4-oxobutanoic acid D38

(S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)succinic acid D39

(S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4- oxobutanoyl)oxy)succinicacid D40

(R)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)succinic acid D41

(R)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4- oxobutanoyl)oxy)succinicacid D42

(S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)succinic acid D43

(R)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)succinic acid D44

(S)-2-(((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)propanoyl)oxy)propanoic acid D45

(S)-2-(((S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl)oxy)propanoic acid D46

(S)-2-(((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)propanoyl)oxy)-2- phenylacetic acid D47

(S)-2-(((S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl)oxy)-2-phenylacetic acid D48

(S)-2-(((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)propanoyl)oxy)succinic acid D49

(S)-2-(((S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl)oxy)succinic acid D50

(R)-2-(((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)propanoyl)oxy)succinic acid D51

(R)-2-(((S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl)oxy)succinic acid D52

(S)-2-(((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)propanoyl)oxy)propanoic acid D53

(S)-2-(((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)propanoyl)oxy)-2- phenylacetic acid D54

(S)-2-(((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)propanoyl)oxy)succinic acid D55

(R)-2-(((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)propanoyl)oxy)succinic acid D56

(S)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)-2- phenylacetoxy)propanoic acid D57

(S)-2-((S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)propanoic acid D58

(S)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)-2-phenylacetoxy)-2- phenylacetic acid D59

(S)-2-((S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)-2-phenylacetic acid D60

(S)-2-(((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-(((S)-2-hydroxypropanoyl)oxy)-4- oxobutanoyl)oxy)propanoyl)oxy)propanoic acidD61

(S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-(((S)-2-hydroxypropanoyl)oxy)-4-oxobutanoyl)oxy)succinic acid D62

(R)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-(((S)-2-hydroxypropanoyl)oxy)-4-oxobutanoyl)oxy)succinic acid D63

(S)-2-(((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-(((S)-2-hydroxypropanoyl)oxy)-4- oxobutanoyl)oxy)propanoyl)oxy)succinic acid D64

(R)-2-(((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-(((S)-2-hydroxypropanoyl)oxy)-4- oxobutanoyl)oxy)propanoyl)oxy)succinic acid D65

(S)-4-(((S)-1-(((S)-1-((S)-1-carboxyethoxy)-1-oxopropan-2-yl)oxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)oxy)-2-hydroxy-4-oxobutanoic acid D66

(S)-2-(((S)-2-(((S)-3-carboxy-3-hydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4- oxobutanoyl)oxy)succnicacid D67

(R)-2-(((S)-2-(((S)-3-carboxy-3-hydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4- oxobutanoyl)oxy)succinicacid D68

(S)-2-(((S)-2-(((S)-2-(((S)-3-carboxy-3-hydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl)oxy)succinic acid D69

(R)-2-(((S)-2-(((S)-2-(((S)-3-carboxy-3-hydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl)oxy)succinic acid D70

(2R,3R)-4-(((S)-1-(((S)-1-((S)-1-carboxyethoxy)-1-oxopropan-2-yl)oxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)oxy)-2,3-dihydroxy-4-oxobutanoic acid D71

(S)-2-(((S)-2-(((2R,3R)-3-carboxy-2,3-dihydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4- oxobutanoyl)oxy)succinicacid D72

(R)-2-(((S)-2-(((2R,3R)-3-carboxy-2,3-dihydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4- oxobutanoyl)oxy)succinicacid D73

(S)-2-(((S)-2-(((S)-2-(((2R,3R)-3-carboxy-2,3-dihydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl)oxy)succinic acid D74

(R)-2-(((S)-2-(((S)-2-(((2R,3R)-3-carboxy-2,3-dihydroxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoyl)oxy)succinic acid D75

(S)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)-2-phenylacetoxy)succinic acid D76

(S)-2-((S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)succinic acid D77

(R)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)-2-phenylacetoxy)succinic acid D78

(R)-2-((S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylacetoxy)succinic acid D79

(S)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)-2- phenylacetoxy)propanoic acid D80

(S)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)-2-phenylacetoxy)-2- phenylacetic acid D81

(S)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)-2-phenylacetoxy)succinic acid D82

(R)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)-2-phenylacetoxy)succinic acid D83

(S)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)propanamido)propanoic acid D84

(S)-2-((S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanamido)propanoic acid D85

(S)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)propanamido)-4- methylpentanoic acid D86

(S)-2-((S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanamido)-4-methylpentanoic acid D87

(S)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)propanamido)succinic acid D88

(S)-2-((S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanamido)succinic acid D89

(R)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)propanamido)succinic acid D90

(R)-2-((S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanamido)succinic acid D91

(S)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)propanamido)propanoic acid D92

(S)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)propanamido)-4- methylpentanoic acid D93

(S)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)propanamido)succinic acid D94

(R)-2-((S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)propanamido)succinic acid D95

(S)-2-(((S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)propanoyl)oxy)-2- phenylacetic acid D96

(S)-2-(((S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)propanoyl)oxy)succinic acid D97

(R)-2-(((S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)propanoyl)oxy)succinic acid D98

(S)-2-((S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)-2- phenylacetoxy)propanoic acid D99

(S)-2-((S)-2-(((2R,3R)-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)-2-phenylacetoxy)-2- phenylacetic acid D100

(S)-2-((S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)-2- phenylacetoxy)succinic acid D101

(R)-2-((S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)-2- phenylacetoxy)succinic acid D102

(S)-2-((S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)propanamido)-4- methylpentanoic acid D103

(S)-2-((S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)propanamido)succinic acid D104

(R)-2-((S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)propanamido)succinic acid

As such, in another aspect, certain embodiments of the present inventionprovide a drug delivery system comprising an abuse-resistant opioidcompound. In such embodiments, as described above, the abuse-resistantopioid compound comprises an opioid covalently bound to a chemicalmoiety.

In another aspect, certain embodiments of the present invention providea method of preventing opioid abuse. In such embodiments, the methodcomprises administering a therapeutically effective amount of an opioidcompound (a compound of one of the formulas described above) to asubject. In some embodiments, the opioid compound may exhibit one ormore of the following advantages over free opioids. The opioid compoundmay prevent overdose by exhibiting a reduced pharmacological activitywhen administered at higher than therapeutic doses, e.g., higher thanthe prescribed dose. Yet when the opioid compound is administered attherapeutic doses, the opioid compound may retain similarpharmacological activity to that achieved by administering unboundopioids, e.g., Opana® ER. Also, the opioid compound may prevent abuse byexhibiting stability under conditions likely to be employed by illicitchemists attempting to release the amphetamine. The opioid compound mayprevent abuse by exhibiting reduced bioavailability when it isadministered via parenteral routes, particularly the intravenous(“shooting”), intranasal (“snorting”), and/or inhalation (“smoking”)routes that are often employed in illicit use. In particular, thechemical moiety X may not release the opioid until the opioid compoundreaches the intestinal tract. Thus, the opioid compound may not beadministered via routes typically associated with opioid abuse. As such,the opioid compound may reduce the euphoric effect associated withopioid abuse. Additionally, the opioid compound may prevent and/orreduce the potential of abuse and/or overdose when the opioid compoundis used in a manner inconsistent with the manufacturer's instructions,e.g., consuming the opioid compound at a higher than therapeutic dose orvia a non-oral route of administration.

According to certain embodiments of the present invention, the opioidcompound remains inactive until oral administration releases the opioid.Without being bound by theory, it is believed that the opioid compoundis inactive because the attachment of the chemical moiety reducesbinding between the opioid and its biological target sites (e.g., opioidreceptors located in the intestinal tract, brain, spinal cord, andperipheral sensory neurons). The opioid compound is activated by oraladministration, that is, the opioid is released from the chemical moietyby hydrolysis, e.g., by enzymes in the intestinal tract. Because oraladministration facilitates activation, activation is reduced or does notoccur when the opioid compound is administered via parenteral routesoften employed by illegal users. Further, it is believed that the opioidcompound is resistant to abuse and/or overdose due to a natural gatingmechanism at the site of hydrolysis, namely the intestinal tract. Thisgating mechanism is thought to allow the release of therapeutic amountsof opioid from the opioid compound but limit the release of higheramounts of opioid.

In another aspect, certain embodiments of the present invention providea method of delivering an active ingredient to a subject. In suchembodiments, the method comprises administering a therapeuticallyeffective amount of an opioid compound to a subject (i.e. an amountsufficient to prevent, ameliorate, and/or eliminate the symptoms of adisease. In some embodiments, this method can be used to treat anydisease that may benefit from opioid-type drugs including, but notlimited to: acute and/or chronic back pain, chronic cancer pain,fibromyalgia, headaches, migraines, acute and/or chronic nerve pain,rheumatoid arthritis, and shortness of breath from cancer orcardiopulmonary syndromes (e.g., COPD).

In accordance with certain embodiments of the present invention, themethod of delivering an active ingredient to a subject may furthercomprise administering at least one adjuvant analgesic in addition toadministering an opioid compound. In such embodiments, the at least oneadjuvant analgesic and the opioid compound can be formulated into asingle dosage form, or they may be formulated together or separatelyamong multiple dosage forms. The at least one adjuvant analgesic and theopioid compound can be administered simultaneously or sequentially inany order. Exemplary combination therapies include the administration ofthe drugs listed in Table 1:

TABLE 1 Exemplary drug therapies contemplated for use in combinationwith an opioid compound Exemplary Drug Condition Class Specificexemplary drugs Back Pain Antidepressant Elavil ®, Prozac ®, Paxil ®,Zoloft ®, Effexor ®, (TCA, SSRI) Serzone ®. Muscle Relaxants Soma ®,Flexeril ®, Skelaxin ®. α-2-Adrenergic Zanaflex ® Agonist Cancer PainSteroid Corticosteroids Fibromyalgia Anticonvulsant Neurontin ®,Lyrica ®, Headache Antidepressant Elavil ®, Prozac ®, Paxil ®, Zoloft ®,Effexor ®, (TCA, SSRI) Serzone ®. Anticonvulsant Depakote ®, Topamax ®.α-2-Adrenergic Zanaflex ® Agonist Migraine Antidepressant Elavil ®,Prozac ®, Paxil ®, Zoloft ®, Effexor ®, (TCA, SSRI) Serzone ®.Anticonvulsant Neurontin ®, Lyrica ®. Steroid Corticosteroids Nerve PainAntidepressant Elavil ®, Prozac ®, Paxil ®, Zoloft ®, Effexor ®, (TCA,SSRI) Serzone ®. Anticonvulsant Neurontin ®, Lyrica ®, Tegretol ®,Dilantin ®, Depakote ®, Klonopin ®, Topamax ®, Lamictal ®.α-2-Adrenergic Zanaflex ®, Catapres ®. Agonist Local AnestheticMexiletine Muscle Relaxant Baclofen NDMA Receptor Dextromethorphan,Ketamine, Amantadine Agonist Topical Pain Lidoderm ®, Capsaicin RelieverRheumatoid Antidepressant Elavil ®, Prozac ®, Paxil ®, Zoloft ®,Effexor ®, Arthritis (TCA, SSRI) Serzone ®. Topical Pain CapsaicinReliever Shortness of Steroid Corticosteroids Breath

In another aspect, certain embodiments of the present invention providea pharmaceutical composition comprising an abuse-resistant opioidcompound and at least one pharmaceutical additive. In such embodiments,the abuse-resistant opioid compound may comprise an opioid covalentlybound to a chemical moiety. Additionally, in such embodiments, the atleast one pharmaceutical additive may include a wide range of materialsincluding, but not limited to diluents and bulking substances, bindersand adhesives, lubricants, glidants, plasticizers, disintegrants,carrier solvents, buffers, colorants, flavorings, sweeteners,preservatives and stabilizers, and other pharmaceutical additives knownin the art.

Diluents increase the bulk of a dosage form and may make the dosage formeasier to handle. Exemplary diluents include, but are not limited to,lactose, dextrose, saccharose, cellulose, starch, and calcium phosphatefor solid dosage forms, e.g., tablets and capsules; olive oil and ethyloleate for soft capsules; water and vegetable oil for liquid dosageforms, e.g., suspensions and emulsions. Additional suitable diluentsinclude, but are not limited to, sucrose, dextrates, dextrin,maltodextrin, microcrystalline cellulose (e.g., Avicel®), microfinecellulose, powdered cellulose, pregelatinized starch (e.g., Starch1500®), calcium phosphate dihydrate, soy polysaccharide (e.g.,Emcosoy®), gelatin, silicon dioxide, calcium sulfate, calcium carbonate,magnesium carbonate, magnesium oxide, sorbitol, mannitol, kaolin,polymethacrylates (e.g., Eudragit®), potassium chloride, sodiumchloride, and talc. In some embodiments, r the ranges for the amount ofdiluent by weight percent may include about 40% to about 90%, about 50%to about 85%, about 55% to about 80%, about 50% to about 60%, andincrements therein.

In embodiments where the pharmaceutical composition is compacted into asolid dosage form, e.g., a tablet, a binder can help the ingredientshold together. Binders include, but are not limited to, sugars such assucrose, lactose, and glucose; corn syrup; soy polysaccharide, gelatin;povidone (e.g., Kollidon®, Plasdone®); Pullulan; cellulose derivativessuch as microcrystalline cellulose, hydroxypropylmethyl cellulose (e.g.,Methocel®), hydroxypropyl cellulose (e.g., Klucel®), ethylcellulose,hydroxyethyl cellulose, carboxymethylcellulose sodium, andmethylcellulose; acrylic and methacrylic acid co-polymers; carbomer(e.g., Carbopol®); polyvinylpolypyrrolidine, polyethylene glycol(Carbowax®); pharmaceutical glaze; alginates such as alginic acid andsodium alginate; gums such as acacia, guar gum, and arabic gums;tragacanth; dextrin and maltodextrin; milk derivatives such as whey;starches such as pregelatinized starch and starch paste; hydrogenatedvegetable oil; and magnesium aluminum silicate.

For tablet dosage forms, the pharmaceutical composition is subjected topressure from a punch and dye. Among other purposes, a lubricant canhelp prevent the composition from sticking to the punch and dyesurfaces. A lubricant can also be used in the coating of a coated dosageform. Lubricants include, but are not limited to, magnesium stearate,calcium stearate, zinc stearate, powdered stearic acid, glycerylmonostearate, glyceryl palmitostearate, glyceryl behenate, silica,magnesium silicate, colloidal silicon dioxide, titanium dioxide, sodiumbenzoate, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenatedvegetable oil, talc, polyethylene glycol, and mineral oil. In certainembodiments, the amount of lubricant by weight percent may be less thanabout 5%, 4%, 3%, 2%, 1.5%, 1%, or 0.5%, or increments therein.

Glidants may improve the flowability of non-compacted solid dosage formsand may improve the accuracy of dosing. Glidants include, but are notlimited to, colloidal silicon dioxide, fumed silicon dioxide, silicagel, talc, magnesium trisilicate, magnesium or calcium stearate,powdered cellulose, starch, and tribasic calcium phosphate.

Plasticizers may include both hydrophobic and hydrophilic plasticizerssuch as, but not limited to, diethyl phthalate, butyl phthalate, diethylsebacate, dibutyl sebacate, triethyl citrate, acetyltriethyl citrate,acetyltributyl citrate, cronotic acid, propylene glycol, castor oil,triacetin, polyethylene glycol, propylene glycol, glycerin, andsorbitol. Plasticizers are particularly useful for pharmaceuticalcompositions containing a polymer and in soft capsules and film-coatedtablets.

Disintegrants can increase the dissolution rate of a pharmaceuticalcomposition. Disintegrants include, but are not limited to, alginatessuch as alginic acid and sodium alginate, carboxymethylcellulosecalcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol®, Primellose®),colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g.,Kollidon®, Polyplasdone®), polyvinylpolypyrrolidine (Plasone-XL®), guargum, magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, starch,pregelatinized starch, sodium starch glycolate (e.g., Explotab®,Primogel®). In some embodiments, the ranges for the amount ofdisintegrant by weight percent may include about 1% to about 10%, about1% to about 5%, about 2% to about 3%, and increments therein.

In embodiments where the pharmaceutical composition is formulated for aliquid dosage form, the pharmaceutical composition may include one ormore solvents. Suitable solvents include, but are not limited to, water;alcohols such as ethanol and isopropyl alcohol; methylene chloride;vegetable oil; polyethylene glycol; propylene glycol; and glycerin.

The pharmaceutical composition may comprise a buffer. Buffers include,but are not limited to, lactic acid, citric acid, acetic acid, sodiumlactate, sodium citrate, and sodium acetate.

Any pharmaceutically acceptable colorant can be used to improveappearance or to help identify the pharmaceutical composition. Exemplarycolorants include D&C Red No. 28, D&C Yellow No. 10, FD&C Blue No. 1,FD&C Red No. 40, FD&C Green #3, FD&C Yellow No. 6, and edible inks.Preferred colors for gelatin capsules include white, medium orange, andlight blue.

Flavorings improve palatability and may be particularly useful forchewable tablet or liquid dosage forms. Flavorings include, but are notlimited to maltol, vanillin, ethyl vanillin, menthol, citric acid,fumaric acid, ethyl maltol, and tartaric acid. Sweeteners include, butare not limited to, sorbitol, saccharin, sodium saccharin, sucrose,aspartame, fructose, mannitol, and invert sugar.

The pharmaceutical compositions of the invention may also include one ormore preservatives and/or stabilizers to improve storagability. Theseinclude, but are not limited to, alcohol, sodium benzoate, butylatedhydroxy toluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid.

Other pharmaceutical additives may include gelling agents such ascolloidal clays; thickening agents such as gum tragacanth and sodiumalginate; wetting agents such as lecithin, polysorbates, andlaurylsulphates; humectants; antioxidants such as vitamin E, caronene,and BHT; adsorbents; effervescing agents; emulsifying agents, viscosityenhancing agents; surface active agents such as sodium lauryl sulfate,dioctyl sodium sulfosuccinate, triethanolamine, polyoxyethylenesorbitan, poloxalkol, and quaternary ammonium salts; and othermiscellaneous excipients such as lactose, mannitol, glucose, fructose,xylose, galactose, sucrose, maltose, xylitol, sorbitol, chloride,sulfate and phosphate salts of potassium, sodium, and magnesium.

The pharmaceutical compositions may be manufactured according to anymethod known to those of skill in the art of pharmaceutical manufacturesuch as, for example, wet granulation, dry granulation, encapsulation,direct compression, slugging, etc. For instance, a pharmaceuticalcomposition may be prepared by mixing the opioid compound with one ormore pharmaceutical additives with an aliquot of liquid, preferablywater, to form a wet granulation. The wet granulation can be dried toobtain granules. The resulting granulation can be milled, screened, andblended with various pharmaceutical additives such as water-insolublepolymers and additional hydrophilic polymers. In some embodiments, anopioid compound may be mixed with a hydrophilic polymer and an aliquotof water, then dried to obtain granules of opioid compound encapsulatedby hydrophilic polymer.

After granulation, the pharmaceutical composition may be encapsulated,e.g., in a gelatin capsule. The gelatin capsule can contain, forexample, kosher gelatin, titanium dioxide, and optional colorants.Alternatively, the pharmaceutical composition may be tableted, e.g.,compressed and optionally coated with a protective coating thatdissolves or disperses in gastric juices.

The pharmaceutical compositions of the invention may be administered bya variety of dosage forms. Any biologically-acceptable dosage form knownin the art, and combinations thereof, are contemplated. Examples ofpreferred dosage forms include, without limitation, tablets includingchewable tablets, film-coated tablets, quick dissolve tablets,effervescent tablets, multi-layer tablets, and bi-layer tablets;caplets; powders including reconstitutable powders; granules;dispersible granules; particles; microparticles; capsules including softand hard gelatin capsules; lozenges; chewable lozenges; cachets; beads;liquids; solutions; suspensions; emulsions; elixirs; and syrups.

The pharmaceutical composition is administered orally. Oraladministration permits the maximum release of opioid, provides sustainedrelease of opioid, and maintains abuse resistance by only releasing theopioid from the chemical moiety upon reaching the intestinal tract.

Oral dosage forms may be presented as discrete units, such as capsules,caplets, or tablets. In certain embodiments, a solid oral dosage formcomprising an opioid compound that is smaller in size compared to asolid oral dosage form containing a therapeutically equivalent amount ofunbound opioid may be used. In some embodiment, the oral dosage form maycomprise a gelatin capsule of size 2, size 3, or smaller (e.g., size 4).The smaller size of the opioid compound dosage forms promotes ease ofswallowing.

Soft gel or soft gelatin capsules may be prepared, for example, bydispersing the formulation in an appropriate vehicle (e.g., vegetableoil) to form a high viscosity mixture. This mixture then is encapsulatedwith a gelatin based film. The industrial units so formed are then driedto a constant weight.

Chewable tablets can be prepared by mixing the opioid compound withexcipients designed to form a relatively soft, flavored tablet dosageform that is intended to be chewed. Conventional tablet machinery andprocedures (e.g., direct compression, granulation, and slugging) can beutilized.

Film-coated tablets can be prepared by coating tablets using techniquessuch as rotating pan coating methods and air suspension methods todeposit a contiguous film layer on a tablet.

Compressed tablets can be prepared by mixing the opioid compound withexcipients that add binding qualities. The mixture can be directlycompressed, or it can be granulated and then compressed.

In other embodiments, the pharmaceutical composition may alternativelybe formulated into a liquid dosage form, such as a solution orsuspension in an aqueous or non-aqueous liquid. The liquid dosage formcan be an emulsion, such as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The oils can be administered by adding thepurified and sterilized liquids to a prepared enteral formula, whichthen is placed in the feeding tube of a patient who is unable toswallow.

For oral administration, fine powders or granules containing diluting,dispersing, and/or surface-active agents can be presented in a draught,in water or a syrup, in capsules or sachets in the dry state, in anon-aqueous suspension wherein suspending agents may be included, or ina suspension in water or a syrup. Liquid dispersions for oraladministration can be syrups, emulsions, or suspensions. The syrups,emulsions, or suspensions can contain a carrier, for example, a naturalgum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, saccharose, saccharose with glycerol, mannitol,sorbitol, and polyvinyl alcohol.

The dose range of the opioid compound for humans will depend on a numberof factors including the age, weight, and condition of the patient.Tablets and other dosage forms provided in discrete units can contain adaily dose, or an appropriate fraction thereof, of one or more opioidcompounds. The dosage form can contain a dose of about 2.5 mg to about500 mg, about 10 mg to about 250 mg, about 10 mg to about 100 mg, about10 mg to about 75 mg, or increments therein of one or more of the opioidcompounds.

In certain embodiments, the pharmaceutical compositions of the inventionmay be administered in a partial, i.e., fractional dose, one or moretimes during a 24 hour period. Fractional, single, double, or othermultiple doses can be taken simultaneously or at different times duringa 24 hour period. The doses can be uneven doses with regard to oneanother or with regard to the individual components at differentadministration times. Preferably, a single dose is administered oncedaily. The dose can be administered in a fed or fasted state.

The dosage units of the pharmaceutical composition can be packagedaccording to market need, for example, as unit doses, rolls, bulkbottles, blister packs, and so forth. The pharmaceutical package, e.g.,blister pack, can further include or be accompanied by indicia allowingindividuals to identify the identity of the pharmaceutical composition,the prescribed indication (e.g., pain), and/or the time periods (e.g.,time of day, day of the week, etc.) for administration. The blister packor other pharmaceutical package can also include a second pharmaceuticalproduct for combination therapy.

EXAMPLES

The present disclosure is further illustrated by the following examples,which in no way should be construed as being limiting. That is, thespecific features described in the following examples are merelyillustrative and not limiting.

Compound Synthesis

The following outlines synthesis of exemplary compounds of theinvention. The suggested methodologies are not intended to be limiting.The variations of these synthetic methodologies or methodologiesreported in literature can be adopted to synthesize molecules within thescope of invention.

HPLC Conditions: Method A

Column: Phenomenex Luna C8(2) column (150×4.6 mm, 5 micron)Mobile Phase A: Water containing 0.1% v/v Trifluoroacetic AcidMobile Phase B: Acetonitrile containing 0.1% v/v Trifluoroacetic Acid

Detection: 254 nm

Method A Gradient Time Flow (min) (mL/min) % A % B 0.0 1.0 100.0 0.015.0 1.0 0.0 100.0 22.0 1.0 0.0 100.0

Method B Gradient Time Flow (min) (mL/min) % A % B 0.0 1.0 100.0 0.012.0 1.0 0.0 30.0 20.0 1.0 0.0 30.0

Preparation 2,5-Dioxopyrrolidin-1-yl oleate

A solution of oleic acid (1.00 g, 3.54 mmol) and N-hydroxysuccinimide(407 mg, 3.54 mmol) in tetrahydrofuran (10 mL) was treated dropwise witha solution of N,N′-dicyclohexylcarbodiimide (730 mg, 3.54 mmol) intetrahydrofuran (10 mL). The mixture was heated at 50° C. under anitrogen atmosphere for 2 h. After this time, the reaction mixture wascooled to room temperature and filtered to remove the soliddicyclohexylurea byproduct. The filtrate was concentrated under reducedpressure and dried under vacuum overnight to provide2,5-dioxopyrrolidin-1-yl oleate (3.54 g, 83%) as a white semi-solid: ¹HNMR (300 MHz, DMSO-d₆) δ 5.32 (m, 2H), 2.81 (s, 4H), 2.65 (t, J=7.2 Hz,2H), 1.99-1.95 (m, 4H), 1.63-1.95 (m, 3H), 1.24-1.18 (m, 19H), 0.85 (t,J=6.3 Hz, 3H).

Preparation of(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yloleate hydrochloride

A suspension of oxycodone (380 mg, 1.20 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled in the ice bath and treateddropwise with a solution of 2,5-dioxopyrrolidin-1-yl octadec-9-enoate(502 mg, 1.32 mmol) in tetrahydrofuran (5 mL) over 15 min. Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. After this time, the reaction mixture was re-cooled in theice bath, treated with saturated aqueous ammonium chloride (50 mL), andextracted with ethyl acetate (2×50 mL). The combined organics werewashed with saturated sodium bicarbonate (2×25 mL) and brine (25 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by column chromatography(silica gel, 0-10% methanol/methylene chloride) followed by reversedphase column chromatography (15 g C18 column, 10-100%acetonitrile/water) to provide(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yloleate (169 mg, 24%) as a colorless oil. Approximately half of thismaterial was dissolved in diethyl ether (1 mL) and treated with a 4.0 Msolution of hydrogen chloride in 1,4-dioxane (0.3 mL). The solution wasdiluted with hexanes (5 mL) and concentrated under reduced pressureuntil a white precipitate formed. The solids were isolated byfiltration, washed with diethyl ether, and dried under vacuum to provide(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yloleate hydrochloride (59 mg, 8%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 9.99 (s, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.70 (d, J=8.1 Hz, 1H),5.57 (apparent d, J=4.5 Hz, 1H), 5.40-5.30 (m, 2H), 5.05 (s, 1H), 4.35(br s, 1H), 3.86 (s, 3H), 3.48 (d, J=10.2 Hz, 1H), 3.27-3.20 (m, 2H),3.10-2.84 (m, 5H), 2.72-2.66 (m, 1H), 2.43 (t, J=7.2 Hz, 2H), 2.12 (d,J=17.7 Hz, 1H), 2.02-2.01 (m, 4H), 1.74-1.61 (m, 4H), 1.32-1.27 (m,20H), 0.88 (t, J=6.6 Hz, 3H); ESI MS m/z 580 [C₃₆H₅₃NO₅+H]⁺; HPLC(Method A) 98.9% (AUC), t_(R)=15.36 min.

Preparation of (S)-Methyl 2-((tert-butoxycarbonyl)oxy)-2-phenylacetate

(S)-Methyl 2-hydroxy-2-phenylacetate (30.0 g, 180 mmol), di-tert-butyldicarbonate (43.3 g, 198 mmol), and zinc acetate (3.96 g, 18.0 mmol)were combined and heated at 55° C. under a nitrogen atmosphere for 48 h.After this time, the reaction mixture was cooled to ambient temperature.The mixture was diluted with water (400 mL) and extracted with methylenechloride (3×200 mL). The combined organics were washed with brine (200mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide (S)-methyl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (39.2 g, 82%) as acolorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.37-7.32 (m, 5H), 5.80 (s,1H), 3.74 (s, 3H), 1.51 (s, 9H).

Preparation of (S)-2-((tert-Butoxycarbonyl)oxy)-2-phenylacetic acid

A solution of (S)-methyl 2-((tert-butoxycarbonyl)oxy)-2-phenylacetate(9.06 g, 34.0 mmol) in a mixture of tetrahydrofuran (106 mL) and water(53 mL) was treated with lithium hydroxide hydrate (4.30 g, 102 mmol)and stirred at ambient temperature for 3 h. After this time, thevolatiles were removed under reduced pressure. The aqueous mixture wasdiluted with water (50 mL) and extracted with diethyl ether (100 mL).The aqueous layer was cooled in an ice bath, acidified to pH ˜3 with 1 Mhydrochloric acid, and extracted with ethyl acetate (3×100 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide(S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetic acid (8.40 g, 98%) as awhite solid: ¹H NMR (500 MHz, CDCl₃) δ 7.50 (7.47 (m, 2H), 7.48-7.37 (m,3H), 5.82 (s, 1H), 1.50 (s, 9H), CO₂H proton not observed.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate

A solution of (S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetic acid (8.02g, 31.8 mmol) in tetrahydrofuran (107 mL) was treated withN-hydroxysuccinimide (4.03 g, 35.0 mmol) andN,N′-dicyclohexylcarbodiimide (7.22 g, 16.4 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (8.20 g, 74%) as a whitepowder: ¹H NMR (500 MHz, DMSO) δ 7.58-7.56 (m, 2H), 7.49-7.45 (m, 3H),6.39 (s, 1H), 2.93-2.76 (m, 4H), 1.45 (s, 9H).

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycabonyl)oxy)-2-phenylacetate

A suspension of oxycodone (0.200 g, 0.634 mmol) in tetrahydrofuran (6.5mL) was cooled in an ice bath and treated dropwise with a 1.0 M solutionof lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.7 mL, 0.7mmol). The mixture was stirred at 0° C. for 15 min and then treateddropwise with a solution of (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (0.190 g, 0.661 mmol) intetrahydrofuran (2 mL). The mixture was stirred at 0° C. for 1 h. Afterthis time, the reaction mixture was treated with saturated aqueousammonium chloride (50 mL) and extracted with ethyl acetate (3×75 mL).The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (silica gel, 0-5% methanol/methylene chloride) toprovide (S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycabonyl)oxy)-2-phenylacetate (0.100 g, 29%) as acolorless oil: ESI MS m/z 550 [C₃₁H₃₅NO₈+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-hydroxy-2-phenylacetate

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycabonyl)oxy)-2-phenylacetate (0.100 g, 0.182 mmol) inmethylene chloride (2 mL) was treated with trifluoroacetic acid (2 mL)and stirred under a nitrogen atmosphere at ambient temperature for 1 h.After this time, the reaction mixture was concentrated under reducedpressure. The residue was triturated with diethyl ether to give a whitepowder. This material was purified by reversed phase columnchromatography (50 g C18 column, 5-50% acetonitrile/water) and freezedried toprovide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-hydroxy-2-phenylacetate 2,2,2-trifluoroacetate (41 mg, 50%) as afluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.14 (br s, 1H),7.46-7.40 (m, 2H), 7.39-7.31 (m, 3H), 6.83 (d, J=8.4 Hz, 2H), 6.73 (d,J=8.1 Hz, 1H), 6.28-6.24 (m, 2H), 5.48-5.45 (m, 1H), 5.27 (d, J=5.7 Hz,1H), 4.92 (s, 1H), 3.68 (s, 3H), 3.64-3.62 (m, 1H), 3.44-3.38 (m, 1H),3.13-3.05 (m, 2H), 2.82 (br s, 3H), 2.27-2.19 (m, 1H), 2.09-2.03 (m,1H), 1.61 (d, J=12.6 Hz, 1H); ESI MS m/z 450 [C₂₆H₂₇NO₆+H]⁺; HPLC(Method A) 98.4% (AUC), t_(R)=8.62 min.

Preparation of (S)-2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid

A solution of (S)-2-hydroxysuccinic acid (25.0 g, 186 mmol) and2-methoxypropene (71.4 mL, 746 mmol) in acetone (400 mL) at 0° C. wasslowly treated with pyridinium p-toluenesulfonate (4.68 g, 18.6 mmol).The reaction mixture was warmed to ambient temperature then heated at35° C. for overnight. After this time, the volatiles were removed underreduced pressure. The residue was triturated in heptane/ethyl acetate(150 mL, 1:1) and filtered. The filtrate was diluted with ethyl acetate(300 mL) and washed with water (150 mL). The organic layer was driedover sodium sulfate, filtered and concentrated at reduced pressure togive (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (27.9 g,86%) as a light brown solid: ¹H NMR (500 MHz, CDCl₃) δ 4.72 (apparent t,J=3.5 Hz, 1H), 3.00 (dd, J=17.0, 3.5 Hz, 1H), 2.56 (dd, J=17.0, 6.5 Hz,1H), 1.57 (s, 3H), 1.50 (s, 3H).

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)aceate

The combined organics were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-methyl 2-((tert-butoxycarbonyl)oxy)propanoate (18.5 g, quantitative)as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 4.98 (apparent t, J=4.5Hz, 1H), 3.34-3.32 (m, 2H), 2.81 (s, 4H), 1.55 (s, 3H), 1.53 (s, 3H).

Preparation of(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate

A suspension of oxycodone (0.500 g, 1.58 mmol) in tetrahydrofuran (10mL) was cooled in an ice bath and treated dropwise with a 1.0 M solutionof lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.74 mL, 1.74mmol). The reaction mixture was stirred at 0° C. for 15 min then wastreated dropwise with a solution of (S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (0.473 g, 1.74 mmol) intetrahydrofuran (5 mL). The reaction was stirred at 0° C. for 3 h. Afterthis time, the reaction mixture was poured into saturated aqueousammonium chloride (50 mL) and extracted with ethyl acetate (3×100 mL).The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (silica gel, 0-5% methanol/methylene chloride) toprovide (4R, 4aS, 7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2,e]isoquinolin-7-yl2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (0.390 g, 52%) as alight yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 6.72 (d, J=8.4 Hz, 1H), 6.62(d, J=8.1 Hz, 1H), 5.69-5.66 (m, 1H), 4.99 (s, 1H), 4.74 (dd, J=6.9,3.6H, 1H), 3.85 (s, 3H), 3.17 (d, J=18.6 Hz, 1H), 3.08 (dd, J=17.1, 3.6Hz, 1H), 2.94-2.86 (m, 2H), 2.68-2.60 (m, 2H), 2.50-2.43 (m, 1H), 2.39(s, 3H), 2.34-2.24 (m, 2H), 2.18-2.14 (m, 2H), 1.62 (s, 3H), 1.56 (s,3H), OH proton not observed; ESI MS m/z 472 [C₂₅H₂₉NO₈+H]⁺.

Preparation(S)-2-Hydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid hydrochloride

A solution of(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2,e]isoquinolin-7-yl2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (0.050 g, 0.11 mmol)in 1,4-dioxane (5 mL) was treated with 4 N hydrogen chloride in1,4-dioxane (0.8 mL) and 4 drops of water. The reaction mixture wasstirred at ambient temperature for 1 h. Additional 4 N hydrogen chloridein 1,4-dioxane (0.25 mL) and water (2 drops) were added and stirringcontinued for another 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was triturated withdiethyl ether, filtered and dried under vacuum at ambient temperaturefor six days to provide(S)-2-hydroxy-4-(((4R,4aS, 7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid hydrochloride (41 mg, 89%) as an off-white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 12.7 (br s, 1H), 9.18 (br s, 1H), 6.82 (d, J=8.1 Hz, 1H),6.75 (d, J=8.1 Hz, 1H), 6.29 (s, 1H), 5.62 (br s, 1H), 5.52 (d, J=4.5Hz, 1H), 4.98 (s, 1H), 4.33 (br s, 1H), 3.76 (s, 3H), 3.57 (s, 3H),3.15-3.06 (m, 2H), 2.89-2.84 (m, 4H), 2.73-2.63 (m, 1H), 2.29 (dd,J=6.3, 18.0 Hz, 1H), 2.33-2.25 (m, 1H), 1.63 (d, J=11.4 Hz, 1H); ESI MSm/z 432 [C₂₂H₂₅NO₈+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylstearate and(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylpalmitate

A suspension of oxycodone (478 mg, 1.52 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (2.0 mL, 2.0 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled in the ice bath and treateddropwise with a solution of 2,5-dioxopyrrolidin-1-yl stearate (644 mg,1.69 mmol) in tetrahydrofuran (5 mL) over 10 min. After addition wascomplete, the mixture was stirred at ambient temperature for 30 min.After this time, the reaction mixture was re-cooled in the ice bath,treated with saturated aqueous ammonium chloride (50 mL), and extractedwith ethyl acetate (2×50 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by column chromatography (silica gel, 0-10%methanol/methyl tert-butyl ether) to provide material contaminated withstearic acid. This material was dissolved in methylene chloride (50 ml),washed with saturated sodium bicarbonate (2×25 mL) and brine (25 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. This residue was purified by reversed phase columnchromatography (50 g C18 column, 30-100% acetonitrile/water) to providetwo compounds. Each compound was freeze dried to afford(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl stearate(92 mg, 10%) as a fluffy white solid: ¹H NMR (300 MHz, CDCl₃) δ 6.71 (d,J=8.1 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 5.57 (dd, J=4.8, 3.9 Hz, 1H),5.01 (s, 1H), 4.72 (brs, 1H), 3.84 (s, 3H), 3.17 (d, J=18.6 Hz, 1H),2.85 (d, J=6.3 Hz, 1H), 2.62 (dd, J=18.9, 6.6 Hz, 1H), 2.47-2.18 (m,8H), 2.16-2.15 (m, 2H), 1.70-1.59 (m, 3H), 1.30-1.25 (m, 28H), 0.88 (t,J=6.3 Hz, 3H); ESI MS m/z 582 [C₃₆H₅₅NO₅+H]⁺; HPLC (Method A) 97.9%(AUC), t_(R)=16.03 min; and(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylpalmitate (105 mg, 12%) as a fluffy white solid: ¹H NMR (300 MHz, CDCl₃)δ 6.71 (d, J=8.1 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 5.57 (dd, J=4.5, 3.6Hz, 1H), 5.01 (s, 1H), 3.84 (s, 3H), 3.17 (d, J=18.6 Hz, 1H), 2.85 (d,J=6.3 Hz, 1H), 2.62 (dd, J=18.6, 6.3 Hz, 1H), 2.47-2.35 (m, 6H),2.32-2.22 (m, 2H), 2.16-2.15 (m, 2H), 1.68-1.59 (m, 3H), 1.30-1.25 (m,24H), 0.88 (t, J=6.3 Hz, 3H), OH proton not observed; ESI MS m/z 554[C₃₄H₅₁NO₅+H]⁺; HPLC (Method A) 96.9% (AUC), t_(R)=15.20 min.

Preparation of (S)-Methyl 2-((tert-butoxycarbonyl)oxy)propanoate

(S)-Methyl 2-hydroxypropanoate (5.01 g, 48.2 mmol), di-tert-butyldicarbonate (11.63 g, 53.29 mmol), and zinc acetate (1.05 g, 4.78 mmol)were combined and heated at 55° C. under a nitrogen atmosphere for 48 h.After this time, the reaction mixture was cooled to room temperature.The mixture was diluted with water (50 mL) and extracted with methylenechloride (2×50 mL). The combined organics were washed with brine (50mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide (S)-methyl 2-((tert-butoxycarbonyl)oxy)propanoate(8.03 g, 82%) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 4.96 (q,J=7.0 Hz, 1H), 3.77 (s, 3H), 1.52 (d, J=6.5 Hz, 3H), 1.50 (s, 9H).

Preparation of (S)-2-((tert-Butoxycarbonyl)oxy)propanoic acid

A solution of (S)-methyl 2-((tert-butoxycarbonyl)oxy)propanoate (7.00 g,34.3 mmol) in tetrahydrofuran (100 mL) and water (50 mL) was treatedwith lithium hydroxide hydrate (1.45 g, 34.5 mmol) and stirred atambient temperature for 16 h. After this time, the volatiles wereremoved under reduced pressure. The aqueous mixture was diluted withwater (50 mL) and extracted with diethyl ether (100 mL). The aqueouslayer was cooled in an ice bath, acidified to pH ˜3 with 0.5 Mhydrochloric acid, and extracted with diethyl ether (3×100 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide of(S)-2-((tert-butoxycarbonyl)oxy)propanoic acid (2.83 g, 43%) as a whitesolid: ¹H NMR (500 MHz, CDCl₃) δ 4.99 (q, J=7.0 Hz, 1H), 1.56 (d, J=7.5Hz, 3H), 1.50 (s, 9H).

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate

A solution of (S)-2-((tert-butoxycarbonyl)oxy)propanoic acid (2.83 g,14.9 mmol) in tetrahydrofuran (50 mL) was treated withN-hydroxysuccinimide (1.88 g, 16.3 mmol) andN,N′-dicyclohexylcarbodiimide (3.38 g, 16.4 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate (3.54 g, 83%) as a white powder:¹H NMR (500 MHz, CDCl₃) δ 5.24 (q, J=7.0 Hz, 1H), 2.84 (s, 4H), 1.69 (d,J=7.0 Hz, 3H), 1.51 (s, 9H).

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)oxy)propanoate

A suspension of oxycodone (201 mg, 0.637 mmol) in tetrahydrofuran (3 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (0.7 mL, 0.7 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled in the ice bath and treateddropwise with a solution of (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate (190 mg, 0.661 mmol) intetrahydrofuran (2 mL). After addition was complete, the mixture wasstirred at ambient temperature for 15 min. After this time, the reactionmixture was treated with saturated aqueous ammonium chloride (10 mL) andextracted with ethyl acetate (2×25 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (silica gel,0-5% methanol/methylene chloride) to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)oxy)propanoate (156 mg, 50%) as a colorlessresidue: ¹H NMR (300 MHz, CDCl₃) 6.71 (d, J=8.1 Hz, 1H), 6.61 (d, J=8.4Hz, 1H), 5.66 (dd, J=5.1, 3.3 Hz, 1H), 5.07-4.99 (m, 2H), 3.84 (s, 3H),3.17 (d, J=18.6 Hz, 1H), 2.85 (d, J=6.3 Hz, 1H), 2.63 (dd, J=18.6, 6.6Hz, 1H), 2.47-2.35 (m, 1H), 2.38 (s, 3H), 2.31-2.22 (m, 2H), 2.18-2.16(2H), 1.63-1.69 (m, 1H), 1.60 (d, J=7.2 Hz, 3H), 1.50 (s, 9H); ESI MSm/z 488 [C₂₆H₃₃NO₈+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-hydroxypropanoate trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)oxy)propanoate (71 mg, 0.15 mmol) in methylenechloride (1 mL) was treated with trifluoroacetic acid (1 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 1 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresidue was triturated with diethyl ether to give a white powder. Thismaterial was purified by reversed phase column chromatography (15 g C18column, 10-100% acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-hydroxypropanoate trifluoroacetic acid salt (36 mg, 51%) as a fluffywhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (s, 1H), 6.86 (d, J=8.1Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.30 (s, 1H), 5.60 (d, J=6.0 Hz, 1H),5.54 (dd, J=6.0, 2.1 Hz, 1H), 5.00 (s, 1H), 4.33-4.24 (m, 1H), 3.75 (s,3H), 3.64 (d, J=6.6 Hz, 1H), 3.43 (d, J=19.8 Hz, 1H), 3.11 (dd, J=18.9,6.6 Hz, 2H), 2.84 (d, J=3.9 Hz, 3H), 2.69-2.57 (m, 1H), 2.49-2.41 (m,1H), 2.32-2.24 (m, 1H), 2.07 (d, J=17.7 Hz, 1H), 1.64 (d, J=11.7 Hz,1H), 1.35 (d, J=6.9 Hz, 3H); ESI MS m/z 388 [C₂₁H₂₅NO₆+H]⁺; HPLC (MethodA) 98.3% (AUC), t_(R)=7.32 min.

Preparation of(S)-2-(((S)-2-((tert-Butoxycarbonyl)amino)propanoyl)oxy)propanoic acid

A solution of (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)amino)propanoate (1.00 g, 3.49 mmol), lacticacid (391 mg, 4.34 mmol), and 4-dimethylaminopyridine (51 mg, 0.42 mmol)in tetrahydrofuran (17 mL) was treated with pyridine (0.33 g, 4.2 mmol)and heated at 50° C. under a nitrogen atmosphere for 17 h. After thistime, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (50 mL) and washed with aqueous 10% citric acid (2×25 mL) andwater (25 mL). The organic layer was extracted with saturated aqueoussodium bicarbonate (2×25 mL). The combined aqueous bicarbonate layerswere acidified to pH ˜2 with 6 N hydrochloric acid and extracted withethyl acetate (4×25 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoic acid(862 mg, 95%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.23-5.17(m, 1H), 5.03-5.01 (m, 1H), 4.38-4.33 (m, 1H), 1.56 (d, J=7.2 Hz, 3H),1.45-1.44 (m, 12H), CO₂H proton not observed; ESIMS m/z 260[C₁₁H₁₉NO₆−H]⁻.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate

A solution of(S)-2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoic acid(820 mg, 3.14 mmol) in tetrahydrofuran (10 mL) was treated withN-hydroxysuccinimide (401 mg, 3.48 mmol) andN,N′-dicyclohexylcarbodiimide (717 mg, 3.48 mmol) and stirred under anitrogen atmosphere for 2 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide(S)-2,5-dioxopyrrolidin-1-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (1.15 g,quantitative) as a colorless crushable foam: ¹H NMR (300 MHz, CDCl₃) δ5.52-5.43 (m, 1H), 5.02-5.00 (m, 1H), 4.42-4.33 (m, 1H), 2.84 (br s,4H), 1.71 (d, J=7.2 Hz, 3H), 1.46-1.44 (m, 12H).

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate

A suspension of oxycodone (480 mg, 1.52 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (1.8 mL, 1.8 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 30 min. The mixture was re-cooled in the ice bath and treateddropwise with a solution of (S)-2,5-dioxopyrrolidin-1-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (601 mg,1.68 mmol) in tetrahydrofuran (5 mL). After addition was complete, themixture was stirred at ambient temperature for 15 min. After this time,the reaction mixture was re-cooled in the ice bath and treated withsaturated aqueous ammonium chloride (25 mL) and extracted with ethylacetate (2×50 mL). The combined organics were washed with saturatedsodium bicarbonate (25 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (silica gel, 0-10% methanol/methylene chloride)followed by reversed phase column chromatography (50 g C18 column,10-100% acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (68 mg,8%) as a fluffy white solid: ESI MS m/z 559 [C₂₉H₃₈N₂O₉+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-aminopropanoyl)oxy)propanoate hydrochloride

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (67 mg,0.12 mmol) in ethyl acetate (1 mL) was treated with a 4.0 M solution ofhydrogen chloride in 1,4-dioxane (1 mL) and stirred under a nitrogenatmosphere at ambient temperature for 3.5 h. After this time, thereaction mixture was diluted with diethyl ether (5 mL). The resultingprecipitate was isolated by filtration, washed with diethyl ether (5mL), and freeze-dried from acetonitrile/water to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-aminopropanoyl)oxy)propanoate hydrochloride (47 mg, 74%) as afluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (br s, 1H), 8.48(s, 3H), 6.87 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.1 Hz, 1H), 6.36 (s, 1H),5.61 (dd, J=6.0, 1.8 Hz, 1H), 5.35 (q, J=6.9 Hz, 1H), 5.01 (s, 1H),4.24-4.22 (m, 1H), 3.76 (s, 3H), 3.69 (d, J=6.0 Hz, 1H), 3.43 (d, J=20.1Hz, 1H), 3.12 (dd, J=19.2, 6.9 Hz, 1H), 2.85 (s, 3H), 2.64-2.57 (m, 1H),2.49-2.27 (m, 2H, partially obscured by solvent peak), 2.06 (apparent d,J=18.0 Hz, 1H), 1.63 (d, J=11.1 Hz, 1H), 1.56 (d, J=6.9 Hz, 3H), 1.48(d, J=7.2 Hz, 3H); ESI MS m/z 459 [C₂₄H₃₀N₂O₇+H]⁺; HPLC (Method A) 95.1%(AUC), t_(R)=6.98 min.

Preparation of(S)-2-(((S)-2-((tert-Butoxycarbonyl)oxy)propanoyl)oxy)propanoic acid

A solution of (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate (1.00 g, 3.48 mmol), lactic acid(376 mg, 4.17 mmol), and 4-dimethylaminopyridine (53 mg, 0.43 mmol) intetrahydrofuran (17 mL) was treated with pyridine (0.33 g, 4.2 mmol) andheated at 50° C. under a nitrogen atmosphere for 48 h. After this time,the reaction mixture was cooled to room temperature and concentratedunder reduced pressure. The residue was dissolved in ethyl acetate (50mL) and washed with aqueous 10% citric acid (2×25 mL) and water (25 mL).The organic layer was extracted with saturated aqueous sodiumbicarbonate (2×25 mL). The combined aqueous bicarbonate layers wereacidified to pH ˜2 with 6 N hydrochloric acid and extracted with ethylacetate (4×25 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide(S)-2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoic acid(659 mg, 72%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.27-5.17(m, 1H), 4.98 (q, J=7.2 Hz, 1H), 1.60-1.55 (m, 6H), 1.50 (s, 9H), CO₂Hproton not observed; ESI MS m/z 261 [C₁₁H₁₈O₇−H]⁻.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoate

A solution of(S)-2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoic acid(659 mg, 2.51 mmol) in tetrahydrofuran (10 mL) was treated withN-hydroxysuccinimide (323 mg, 2.81 mmol) andN,N′-dicyclohexylcarbodiimide (573 mg, 2.78 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide(S)-2,5-dioxopyrrolidin-1-yl2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoate (813 g,90%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ 5.57-5.47 (m, 1H),5.02-4.94 (m, 1H), 2.84 (br s, 4H), 1.73-1.69 (m, 3H), 1.60-1.55 (m,3H), 1.49 (s, 9H).

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoate

A suspension of oxycodone (602 mg, 1.91 mmol) in tetrahydrofuran (6 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (2.3 mL, 2.3 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled in the ice bath and treateddropwise with a solution of (S)-2,5-dioxopyrrolidin-1-yl2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoate (813 mg,2.26 mmol) in tetrahydrofuran (6 mL). After addition was complete, themixture was stirred at ambient temperature for 15 min. After this time,the reaction mixture was re-cooled in the ice bath and treated withsaturated aqueous ammonium chloride (10 mL) and extracted with ethylacetate (2×25 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (silica gel, 0-10% methanol/methylenechloride) followed by reversed phase column chromatography (50 g C18column, 10-100% acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoate (98 mg, 9%)as a fluffy white solid: ESI MS m/z 560 [C₂₉H₃₇NO₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-hydroxypropanoyl)oxy)propanoate trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoate (94 mg,0.17 mmol) in methylene chloride (2 mL) was treated with trifluoroaceticacid (1 mL) and stirred under a nitrogen atmosphere at ambienttemperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (C18 column, 10-100%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-hydroxypropanoyl)oxy)propanoate trifluoroacetic acid salt (51mg, 54%) as a fluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (brs, 1H), 6.86 (d, J=8.1 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.30 (s, 1H),5.59 (dd, J=5.7, 1.8 Hz, 1H), 5.50 (br s, 1H), 5.17 (q, J=6.9 Hz, 1H),5.00 (s, 1H), 4.25-4.22 (m, 1H), 3.75 (s, 3H), 3.65 (d, J=6.0 Hz, 1H),3.46-3.38 (m, 1H, partially obscured by water peak), 3.16-3.07 (m, 2H),2.84 (apparent d, J=5.1 Hz, 3H), 2.69-2.57 (m, 1H), 2.49-2.26 (m, 2H,partially obscured by solvent peak), 2.07 (apparent d, J=18.0 Hz, 1H),1.65 (d, J=11.4 Hz, 1H), 1.51 (d, J=11.4 Hz, 3H), 1.31 (d, J=6.6 Hz,3H); ESI MS m/z 460 [C₂₄H₂₉NO₈+H]⁺.

Preparation of (2E,4E)-2,5-Dioxopyrrolidin-1-yl hexa-2,4-dienoate

A solution of (2E,4E)-hexa-2,4-dienoic acid (2.00 g, 17.8 mmol) intetrahydrofuran (50 mL) was treated with N-hydroxysuccinimide (2.26 g,19.6 mmol) and N,N′-dicyclohexylcarbodiimide (4.04 g, 19.6 mmol) andstirred under a nitrogen atmosphere for 2.5 h. After this time, thereaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether, and the combinedfiltrate and washings were concentrated under reduced pressure toprovide (2E,4E)-2,5-dioxopyrrolidin-1-yl hexa-2,4-dienoate (5.14 g,quantitative) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.53-5.44 (m,1H), 6.31-6.27 (m, 2H), 5.93 (d, J=15.3 Hz, 1H), 2.85 (s, 4H), 1.91 (d,J=5.4 Hz, 3H).

Preparation of(2E,4E)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylhexa-2,4-dienoate

A suspension of oxycodone (487 mg, 1.54 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (1.9 mL, 1.9 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled in the ice bath and treateddropwise with a solution of (2E,4E)-2,5-dioxopyrrolidin-1-ylhexa-2,4-dienoate (391 mg, 1.87 mmol) in tetrahydrofuran (5 mL). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. After this time, the reaction mixture was re-cooled in theice bath and treated with saturated aqueous ammonium chloride (50 mL)and extracted with ethyl acetate (2×50 mL). The combined organics werewashed with saturated sodium bicarbonate (25 mL) and brine (25 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by column chromatography(silica gel, 0-10% methanol/methylene chloride) followed by reversedphase column chromatography (50 g C18 column, 10-100%acetonitrile/water) and freeze dried to provide(2E,4E)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylhexa-2,4-dienoate (69 mg, 11%) as a fluffy white solid: ¹H NMR (300 MHz,CDCl₃) δ 7.35-7.26 (m, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.1 Hz,1H), 6.26-6.10 (m, 2H), 5.85 (d, J=15.3 Hz, 1H), 5.64 (overlapping dd,J=3.9 Hz, 1H), 5.06 (s, 1H), 4.72 (br s, 1H), 3.84 (s, 3H), 3.18 (d,J=18.6 Hz, 1H), 2.86 (d, J=6.3 Hz, 1H), 2.63 (dd, J=18.6, 6.3 Hz, 1H),2.47-2.42 (m, 1H), 2.38 (s, 3H), 2.33-2.19 (m, 2H), 2.18-2.16 (m, 2H),1.87 (d, J=5.4 Hz, 3H), 1.63 (dd, J=13.5, 3.0 Hz, 1H); ESI MS m/z 410[C₂₄H₂₇NO₅+H]⁺; HPLC (Method A) >99% (AUC), t_(R)=9.74 min.

Preparation of (S)-tert-Butyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate

A solution of (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid(7.50 g, 43.1 mmol) in methylene chloride (150 mL) was treated withN,N′-dicyclohexylcarbodiimide (10.7 g, 51.7 mmol),4-dimethylaminopyridine (1.60 g, 12.9 mmol), and tert-butyl alcohol (6.2mL, 64.7 mmol) and stirred under a nitrogen atmosphere for 2 h. Afterthis time, the reaction mixture was filtered to remove the soliddicyclohexylurea byproduct. The filtrate was concentrated under reducedpressure. The crude residue was purified by column chromatography(silica gel, 0-10% ethyl acetate/heptanes) to provide (S)-tert-butyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (7.2 g, 73%) as anoff-white solid: ¹H NMR (300 MHz, CDCl₃) δ 4.66 (dd, J=6.3, 3.9 Hz, 1H),2.84 (dd, J=16.8, 3.9 Hz, 1H), 2.72 (dd, J=16.8, 6.3 Hz, 1H), 1.63 (s,3H), 1.56 (s, 3H), 1.47 (s, 9H).

Preparation of (S)-4-tert-Butyl 1-methyl 2-hydroxysuccinate

A solution of (S)-tert-butyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (6.80 g, 29.6 mmol) inmethanol (100 mL) was cooled in an ice bath and treated portion-wiseover 10 min with anhydrous sodium methoxide (1.76 g, 32.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1.5 h. Afterthis time, the reaction mixture was treated with saturated aqueousammonium chloride (100 mL) and extracted with ethyl acetate (3×100 mL).The combined organics were dried over sodium sulfate, filtered,concentrated under reduced pressure, and dried under vacuum to provide(S)-4-tert-butyl 1-methyl 2-hydroxysuccinate (5.2 g, 86%) as a yellowoil: ¹H NMR (300 MHz, CDCl₃) δ 4.44 (dd, J=10.5, 5.4 Hz, 1H), 3.81 (s,3H), 3.22 (d, J=5.4 Hz, 1H), 2.87-2.64 (m, 2H), 1.45 (s, 9H).

Preparation of (S)-4-tert-Butyl 1-methyl2-((tert-butoxycarbonyl)oxy)succinate

A solution of (S)-4-tert-butyl 1-methyl 2-hydroxysuccinate (5.30 g, 26.0mmol) in methylene chloride (150 mL) was cooled in an ice bath under anitrogen atmosphere and treated with 4-dimethylaminopyridine (0.317 g,2.60 mmol) followed by di-tert-butyl dicarbonate (8.50 g, 40.0 mmol).After 2-3 min, the ice bath was removed, and the mixture was stirred atambient temperature for 2 h. After this time, the reaction mixture wasconcentrated under reduced pressure and purified by columnchromatography (silica gel, 0-5% ethyl acetate/heptanes) to provide(S)-4-tert-butyl 1-methyl 2-((tert-butoxycarbonyl)oxy)succinate (6.6 g,83%) as a light yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.32 (dd, J=6.9,6.0 Hz, 1H), 3.78 (s, 3H), 2.81-2.79 (m, 2H), 1.50 (s, 9H), 1.45 (s,9H).

Preparation of(S)-4-(tert-Butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoic acid

A solution of (S)-4-tert-butyl 1-methyl2-((tert-butoxycarbonyl)oxy)succinate (6.60 g, 21.7 mmol) intetrahydrofuran (74 mL) and water (37 mL) was cooled in an ice bath,treated with lithium hydroxide hydrate (1.09 g, 26.1 mmol), and stirredat 0° C. for 3 h. After this time, the reaction mixture was concentratedto remove the volatiles, acidified at 0° C. to pH ˜3, and extracted withethyl acetate (3×100 mL). The combined organics were dried over sodiumsulfate, filtered, concentrated under reduced pressure, and dried undervacuum to provide(S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoic acid (5.7g, 90%): ¹H NMR (300 MHz, CDCl₃) δ 5.32 (apparent t, J=6.0 Hz, 1H), 2.85(apparent d, J=6.0 Hz, 2H), 1.50 (s, 9H), 1.46 (s, 9H), CO₂H proton notobserved.

Preparation of (S)-4-tert-Butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)oxy)succinate

A solution of(S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoic acid (525mg, 1.81 mmol) in tetrahydrofuran (10 mL) was treated withN-hydroxysuccinimide (292 mg, 2.53 mmol) andN,N′-dicyclohexylcarbodiimide (523 mg, 2.53 mmol) and stirred under anitrogen atmosphere for 1 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with tetrahydrofuran (25 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with tetrahydrofuran (25 mL) and filtered to remove thesolids. The filtrate was concentrated under reduced pressure. Theresidue was triturated with diethyl ether and filtered to remove thesolids. The filtrate was concentrated under reduced pressure and driedunder vacuum to provide (S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)oxy)succinate (702 mg, quantitative) as a lightyellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.61 (dd, J=8.1, 4.8 Hz, 1H),2.98-2.94 (m, 2H), 2.84 (s, 4H), 1.51 (s, 9H), 1.47 (s, 9H).

Preparation of (S)-4-tert-Butyl1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate

A suspension of oxycodone (0.438 g, 1.39 mmol) in tetrahydrofuran (10mL) was cooled in an ice bath and treated dropwise with a 1.0 M solutionof lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.80 mL, 1.80mmol). The reaction mixture was stirred at 0° C. for 15 min then wastreated dropwise with a solution of (S)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate(0.700 g, 1.81 mmol) in tetrahydrofuran (6 mL). The reaction mixture wasstirred at 0° C. for 1 h. After this time, the reaction mixture waspoured into saturated aqueous ammonium chloride (100 mL) and extractedwith ethyl acetate (3×100 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (50 gC18 column, 5-80% acetonitrile/water) and freeze dried toprovide(S)-4-tert-butyl1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate (0.133 g, 16%) as a white solid:ESI MS m/z 588 [C₃₁H₄₁NO₁₀+H]⁺.

Preparation of(S)-3-Hydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of (S)-4-tert-butyl1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate (0.070 g, 0.12 mmol) indichloromethane (8 mL) was treated with trifluoroacetic acid (2.5 mL).The reaction mixture was stirred at ambient temperature for 1 h. Afterthis time, the reaction mixture was concentrated under reduced pressure.The residue was triturated with diethyl ether, filtered and lyophilizedtoprovide(S)-3-hydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (0.044 g, 86%) as an off-white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 12.43 (br s, 1H), 9.18 (br s, 1H), 6.86 (d,J=8.4 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.29 (br s, 1H), 5.90 (br s, 1H),5.55-5.54 (m, 1H), 4.97 (s, 1H), 4.47 (br s, 1H), 3.75 (s, 3H), 3.62 (s,1H), 3.45-3.37 (m, 1H), 3.12-3.06 (m, 2H), 2.83 (s, 3H), 2.74-2.53 (m,3H), 2.33-2.22 (m, 1H), 2.07 (d, J=18.3 Hz, 1H), 1.63 (d, J=12.3 Hz,1H), one proton obscured by solvent peaks; ESI MS m/z 432[C₂₂H₂₅NO₈+H]⁺.

Preparation of (R)-Methyl 2-((tert-butoxycarbonyl)oxy)-2-phenylacetate

(R)-Methyl 2-hydroxy-2-phenylacetate (20.0 g, 120 mmol), di-tert-butyldicarbonate (34.1 g, 156 mmol), and zinc acetate (3.96 g, 18.0 mmol)were combined and heated at 55° C. overnight under a nitrogenatmosphere. After this time, the reaction mixture was cooled to roomtemperature. The mixture was diluted with water (300 mL) and extractedwith methylene chloride (3×150 mL). The combined organics were washedwith brine (150 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide (R)-methyl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (31.4 g, 98%) as acolorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.49-7.46 (m, 2H), 7.40-7.36(m, 3H), 5.80 (s, 1H), 3.74 (s, 3H), 1.51 (s, 9H).

Preparation of (R)-2-((tert-Butoxycarbonyl)oxy)-2-phenylacetic acid

A solution of (R)-methyl 2-((tert-butoxycarbonyl)oxy)-2-phenylacetate(30.0 g, 110 mmol) in a mixture of tetrahydrofuran (300 mL) and water(150 mL) was treated with lithium hydroxide hydrate (9.45 g, 220 mmol)and stirred at ambient temperature for 3 h. After this time, thevolatiles were removed under reduced pressure. The aqueous mixture wasdiluted with water (50 mL) and extracted with diethyl ether (150 mL).The aqueous layer was cooled in an ice bath, acidified to pH ˜3 with 1.0M hydrochloric acid, and extracted with ethyl acetate (3×150 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide(R)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetic acid (16.8 g, 61%) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 7.51-7.44 (m, 2H), 7.41-7.36 (m,3H), 5.25 (s, 1H), 1.51 (s, 9H), CO₂H proton not observed.

Preparation of (R)-2,5-Dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate

A solution of (R)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetic acid (7.78g, 30.8 mmol) in tetrahydrofuran (110 mL) was treated withN-hydroxysuccinimide (3.90 g, 34.0 mmol) andN,N′-dicyclohexylcarbodiimide (7.00 g, 34.0 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (R)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (8.50 g, 79%) as a whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 7.57-7.55 (m, 2H), 7.44-7.42 (m, 3H),6.15 (s, 1H), 2.80 (m, 4H), 1.52 (s, 9H).

Preparation of(R)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycabonyl)oxy)-2-phenylacetate

A suspension of oxycodone (0.350 g, 1.11 mmol) in tetrahydrofuran (8 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.3 mL, 1.3 mmol).The mixture was stirred at 0° C. for 15 min and then treated dropwisewith a solution of (R)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (0.465 g, 1.33 mmol) intetrahydrofuran (4 mL). The reaction mixture was stirred at 0° C. for 1h. After this time, the mixture was poured into saturated aqueousammonium chloride (75 mL) and extracted with ethyl acetate (2×100 mL).The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (silica gel, 0-5% methanol/methylene chloride) toprovide(R)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycabonyl)oxy)-2-phenylacetate (0.130 g, 21%) as a lightyellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.53 (m, 2H), 7.40-7.37 (m,3H), 6.68 (d, J=8.1 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 5.90 (s, 1H), 5.56(apparent t, J=3.6 Hz, 1H), 4.89 (s, 1H), 3.77 (s, 3H), 3.14 (d, J=18.6Hz, 1H), 2.83 (d, J=6.3 Hz, 1H), 2.60 (dd, J=18.6, 6.3 Hz, 1H),2.44-2.40 (m, 1H), 2.36 (s, 3H), 2.27-2.12 (m, 4H), 1.35-1.55 (m, 2H),1.50 (s, 9H).

Preparation of(R)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-hydroxy-2-phenylacetate trifluoroacetic acid salt

A solution of(R)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycabonyl)oxy)-2-phenylacetate (0.120 g, 0.218 mmol) inmethylene chloride (3 mL) was treated with trifluoroacetic acid (2 mL)and stirred at ambient temperature for 1 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas triturated with diethyl ether to give a white powder. The powder wasdissolved in water and freeze dried to provide(R)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-hydroxy-2-phenylacetate trifluoroacetic acid salt (83 mg, 50%) as afluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (br s, 1H),7.49-7.33 (m, 5H), 6.84 (d, J=8.1 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H),6.28-6.24 (m, 2H), 5.44-5.41 (m, 1H), 5.28 (d, J=5.1 Hz, 1H), 4.95 (s,1H), 3.68 (s, 3H), 3.64-3.62 (m, 1H), 3.44-3.35 (m, 1H), 3.13-3.04 (m,2H), 2.83 (s, 3H), 2.69-2.54 (m, 1H), 2.44-2.43 (m, 1H), 2.34 (dd,J=18.0, 5.4 Hz, 1H), 2.04 (d, J=18.0 Hz, 1H); ESI MS m/z 450[C₂₆H₂₇NO₆+H]⁺; HPLC (Method A) 95.2% (AUC), t_(R)=8.62 min.

Preparation of(S)-2-(((S)-2-((tert-Butoxycarbonyl)oxy)propanoyl)oxy)-2-phenylaceticacid

A solution of (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate (2.00 g, 6.96 mmol), mandelicacid (1.28 g, 8.41 mmol), and 4-dimethylaminopyridine (87 mg, 0.71 mmol)in tetrahydrofuran (30 mL) was treated with pyridine (0.67 mL, 8.3 mmol)and heated at 50° C. under a nitrogen atmosphere for 20 h. After thistime, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (50 mL) and washed with aqueous 10% citric acid (2×25 mL) andwater (25 mL). The organic layer was extracted with saturated aqueoussodium bicarbonate (2×25 mL). The combined aqueous bicarbonate layerswere acidified to pH ˜2 with 6 N hydrochloric acid and extracted withethyl acetate (4×25 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)-2-phenylaceticacid (1.71 g, 76%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ7.48-7.36 (m, 5H), 6.00 (s, 1H), 5.06 (q, J=6.9 Hz, 1H), 1.62 (d, J=6.9Hz, 3H), 1.48 (s, 9H), CO₂H proton not observed; ESI MS m/z 647[(2×C₁₆H₂₀O₇)−H]⁻.

Preparation of(S)—(S)-2-((2,5-Dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl2-((tert-butoxycarbonyl)oxy)propanoate

A solution of(S)-2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)-2-phenylaceticacid (1.71 g, 5.27 mmol) in tetrahydrofuran (20 mL) was treated withN-hydroxysuccinimide (667 mg, 5.80 mmol) andN,N′-dicyclohexylcarbodiimide (1.21 g, 5.86 mmol) and stirred under anitrogen atmosphere for 2.5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide(S)—(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl2-((tert-butoxycarbonyl)oxy)propanoate (2.21 g, 99%) as an whitecrushable foam: ¹H NMR (300 MHz, CDCl₃) δ 7.55-7.51 (m, 2H), 7.47-7.42(m, 3H), 6.39 (s, 1H), 5.05 (q, J=7.2 Hz, 1H), 2.80 (s, 4H), 1.61 (d,J=7.2 Hz, 3H), 1.48 (s, 9H).

Preparation of(S)—(S)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-((tert-butoxycarbonyl)oxy)propanoate

A suspension of oxycodone (503 mg, 1.60 mmol) in tetrahydrofuran (6 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (1.9 mL, 1.9 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled in the ice bath and treateddropwise with a solution of(S)—(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl2-((tert-butoxycarbonyl)oxy)propanoate (806 mg, 1.91 mmol) intetrahydrofuran (6 mL). After addition was complete, the mixture wasstirred at ambient temperature for 10 min. After this time, the reactionmixture was re-cooled in the ice bath and treated with saturated aqueousammonium chloride (50 mL) and extracted with ethyl acetate (2×50 mL).The combined organics were washed with saturated sodium bicarbonate (25mL) and brine (25 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (silica gel, 0-10% methanol/methylene chloride)followed by reversed phase column chromatography (50 g C18 column,10-100% acetonitrile/water) and freeze dried to provide(S)—(S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-((tert-butoxycarbonyl)oxy)propanoate (51 mg, 5%) as a fluffy whitesolid: ESI MS m/z 622 [C₃₄H₃₉NO₁₀+H]⁺.

Preparation of(S)—(S)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-hydroxypropanoate trifluoroacetic acid salt

A solution of(S)—(S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-((tert-butoxycarbonyl)oxy)propanoate (50 mg, 0.080 mmol) in methylenechloride (2 mL) was treated with trifluoroacetic acid (1 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 30 min. Afterthis time, the reaction mixture was concentrated under reduced pressure.The residue was purified by reversed phase column chromatography (C18column, 10-100% acetonitrile/water) and freeze dried to provide(S)—(S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-hydroxypropanoate trifluoroacetic acid salt (23 mg, 46%) as a fluffywhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (br s, 1H), 7.57-7.55 (m,2H), 7.48-7.45 (m, 3H), 6.81 (d, J=8.1 Hz, 1H), 6.72 (d, J=8.1 Hz, 1H),6.31 (br s, 1H), 6.15 (s, 1H), 5.57-5.53 (m, 2H), 4.94 (s, 1H),4.34-4.26 (m, 1H), 3.64 (br s, 4H), 3.44-3.37 (m, 1H, partially obscuredby water peak), 3.13-3.05 (m, 2H), 2.82 (s, 3H), 2.62-2.57 (m, 1H),2.49-2.39 (m, 1H, partially obscured by solvent peak), 2.30-2.22 (m,1H), 2.08-2.02 (m, 1H), 1.62 (d, J=12.0 Hz, 1H), 1.37 (d, J=6.6 Hz, 3H);ESI MS m/z 522 [C₂₉H₃₁NO₈+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)amino)propanoate

A suspension of oxycodone (0.500 g, 1.58 mmol) in tetrahydrofuran (10mL) was cooled in an ice bath and treated dropwise with a 1.0 M solutionof lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.7 mL, 0.7mmol). The mixture was stirred at 0° C. for 15 min and then treateddropwise with a solution of (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)amino)propanoate (0.904 g, 3.16 mmol) intetrahydrofuran (10 mL). The mixture was stirred 0° C. for 1 h. Afterthis time, the reaction mixture was treated with saturated aqueousammonium chloride (75 mL) and extracted with ethyl acetate (2×100 mL).The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified byreversed phase chromatography (C18, 10-80% acetonitrile/water) toprovide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)amino)propanoate (0.225 g, 29%) as a whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 6.71 (d, J=8.1 Hz, 1H), 6.62 (d, J=8.4Hz, 1H), 5.65-5.62 (m, 1H), 5.05 (br s, 1H), 4.99 (s, 1H), 4.45-4.35 (m,1H), 3.84 (s, 3H), 3.17 (d, J=18.6 Hz, 1H), 2.86 (d, J=6.3 Hz, 1H), 2.63(dd, J=18.9, 6.3 Hz, 1H), 2.47-2.42 (m, 1H), 2.38 (s, 3H), 2.35-2.22 (m,2H), 2.18-2.16 (m, 2H), 1.64-1.59 (m, 1H), 1.48 (d, J=7.5 Hz, 3H), 1.45(s, 9H), OH proton not observed.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-aminopropanoate bis(trifluoroacetic acid salt)

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)amino)propanoate (0.200 g, 0.410 mmol) inmethylene chloride (6 mL) was treated with trifluoroacetic acid (3 mL)and stirred under a nitrogen atmosphere at ambient temperature for 0.5h. After this time, the reaction mixture was concentrated under reducedpressure to give(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-aminopropanoate bis(trifluoroacetic acid salt) (0.343 g, quantitative)as a light yellow oil: ESI MS m/z 387 [C₂₁H₂₆N₂O₅+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-aminopropanoate bis(trifluoroacetic acid salt) (0.252 g, 0.411 mmol)in methylene chloride (8 mL) was cooled in an ice bath and treated withN,N-diisopropylethylamine (0.77 mL, 4.44 mmol) and(S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)oxy)propanoate(0.382 g, 1.33 mmol). The ice bath was removed, and the mixture wasstirred at ambient temperature for 2 h. After this time, the reactionmixture was concentrated under reduced pressure. The residue was dilutedin ethyl acetate (100 mL) and successively washed with 10% citric acid(75 mL), saturated sodium bicarbonate (75 mL) and brine (75 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude residue was purified by columnchromatography (silica gel, 0-4% methylene chloride/methanol) toprovide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate (0.138 g, 60%)as a white foam: ESI MS m/z 559 [C₂₉H₃₈N₂O₉+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-hydroxypropanamido)propanoate trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate (0.080 g, 0.14mmol) in methylene chloride (3 mL) was treated with trifluoroacetic acid(1.5 mL) and stirred at ambient temperature for 1 h. After this time,the reaction mixture was concentrated under reduced pressure. Theresidue was triturated with a mixture of methylene chloride/diethylether (1:1) and filtered to give(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-hydroxypropanamido)propanoatetrifluoroacetic acid salt (0.044mg, 67%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (br s, 1H),8.09 (d, J=6.9 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H),6.28 (s, 1H), 5.53-5.50 (m, 1H), 5.00 (s, 1H), 4.39-4.34 (m, 1H),4.03-3.99 (m, 1H), 3.75 (s, 3H), 3.64 (d, J=5.7 Hz, 1H), 3.50-3.35 (m,2H), 3.13-3.06 (m, 2H), 2.84 (d, J=4.5 Hz, 3H), 2.75-2.55 (m, 1H),2.32-2.24 (m, 1H), 2.06 (d, J=18.0 Hz, 1H), 1.59 (d, J=11.7 Hz, 1H),1.40 (d, J=7.2 Hz, 3H), 1.22 (d, J=10.5 Hz, 3H); ESI MS m/z 459[C₂₄H₃₀N₂O₇+H]⁺.

Preparation of(S)-2-(((S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carbonyl)oxy)propanoicacid

A solution of (S)-1-tert-butyl 2-(2,5-dioxopyrrolidin-1-yl)pyrrolidine-1,2-dicarboxylate (2.01 g, 6.44 mmol), lactic acid (699 mg,7.76 mmol), and 4-dimethylaminopyridine (82 mg, 0.67 mmol) intetrahydrofuran (30 mL) was treated with pyridine (0.62 mL, 7.7 mmol)and heated at 50° C. under a nitrogen atmosphere for 20 h. After thistime, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (50 mL) and washed with aqueous 10% citric acid (2×25 mL) andwater (25 mL). The organic layer was extracted with saturated aqueoussodium bicarbonate (2×25 mL). The combined aqueous bicarbonate layerswere acidified to pH ˜2 with 6 N hydrochloric acid and extracted withethyl acetate (4×25 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-2-(((S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carbonyl)oxy)propanoicacid (646 mg, 35%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃, Mixtureof isomers) δ 5.29 (q, J=7.2 Hz, 0.51H), 5.21-5.14 (m, 0.49H), 4.38 (dd,J=8.4, 4.8 Hz, 0.51H), 4.38 (dd, J=8.4, 3.9 Hz, 0.49H), 3.62-3.36 (m,2H), 2.34-2.22 (m, 1H), 2.19-2.06 (m, 1H), 1.98-1.87 (m, 2H), 1.57-1.41(m, 12H), CO₂H proton not observed; ESI MS m/z 573 [(2×C₁₃H₂₁NO₆)−H]⁻.

Preparation of (S)-1-tert-Butyl2-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)pyrrolidine-1,2-dicarboxylate

A solution of(S)-2-(((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)oxy)propanoicacid (640 mg, 2.23 mmol) in tetrahydrofuran (10 mL) was treated withN-hydroxysuccinimide (283 mg, 2.46 mmol) andN,N′-dicyclohexylcarbodiimide (511 mg, 2.48 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide (S)-1-tert-butyl2-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)pyrrolidine-1,2-dicarboxylate (957 mg, quantitative) as a tan foam: ¹HNMR (300 MHz, CDCl₃, Mixture of isomers) δ 5.48 (q, J=6.9 Hz, 1H), 4.41(dd, J=8.4, 3.9 Hz, 0.50H), 4.31 (dd, J=8.4, 3.9 Hz, 0.50H), 3.60-3.37(m, 2H), 2.85-2.84 (m, 4H), 2.27-2.11 (m, 2H), 1.98-1.89 (m, 2H), 1.70(d, J=6.9 Hz, 3H), 1.45 (s, 4.5H), 1.43 (s, 4.5H).

Preparation of (S)-1-tert-Butyl2-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)pyrrolidine-1,2-dicarboxylate

A suspension of oxycodone (634 mg, 2.01 mmol) in tetrahydrofuran (7 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (2.4 mL, 2.4 mmol). Afteraddition was complete, the mixture was stirred in the ice bath for 5 minand at ambient temperature for 5 min. The mixture was re-cooled in anice/brine bath and treated dropwise with a solution of (S)-1-tert-butyl2-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)pyrrolidine-1,2-dicarboxylate (932 mg, 2.43 mmol) in tetrahydrofuran (7mL). After addition was complete, the mixture was stirred in theice/brine bath for 20 min. After this time, the reaction mixture wastreated with saturated aqueous ammonium chloride (50 mL) and extractedwith ethyl acetate (2×50 mL). The combined organics were washed withsaturated sodium bicarbonate (50 mL) and brine (50 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by column chromatography (silica gel, 0-10%methanol/methylene chloride) followed by reversed phase columnchromatography (150 g C18 column, 20-100% acetonitrile/water) and freezedried to provide (S)-1-tert-butyl2-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)pyrrolidine-1,2-dicarboxylate (185 mg, 16%) as a fluffy white solid: ESIMS m/z 585 [C₃₁H₄₀N₂O₉+H]⁺.

Preparation of(S)—(S)-1-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-ylpyrrolidine-2-carboxylate dihydrochloride

A solution of (S)-1-tert-butyl2-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)pyrrolidine-1,2-dicarboxylate (88 mg, 0.15 mmol) in ethyl acetate (1 mL)was treated with a 4.0 M solution of hydrogen chloride in 1,4-dioxane (1mL) and stirred under a nitrogen atmosphere at ambient temperature for 1h. After this time, the reaction mixture was diluted with diethyl etherand sonicated to produce a solid precipitate. The solid was isolated byfiltration, washed with diethyl ether, and dried under vacuum to provide(S)—(S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-ylpyrrolidine-2-carboxylate dihydrochloride (90 mg, quantitative) as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.93 (br s, 1H), 9.22 (br s,1H), 9.02 (br s, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.1 Hz, 1H),6.35 (s, 1H), 5.62 (dd, J=5.7, 1.8 Hz, 1H), 5.35 (q, J=7.2 Hz, 1H), 4.99(s, 1H), 4.54 (br s, 1H), 3.75 (s, 3H), 3.69 (d, J=5.7 Hz, 1H),3.42-3.37 (m, 1H, partially obscured by water peak), 3.25 (br s, 2H),3.16-3.07 (m, 2H), 2.85 (apparent d, J=4.8 Hz, 3H), 2.65-2.57 (m, 1H),2.49-2.27 (m, 3H, partially obscured by solvent peak), 2.18-1.88 (m,4H), 1.63 (d, J=12.0 Hz, 1H), 1.57 (d, J=7.2 Hz, 3H); ESI MS m/z 485[C₂₆H₃₂N₂O₇+H]⁺; HPLC (Method A) 98.0% (AUC), t_(R)=7.07 min.

Preparation of(S)-3-(1-(tert-Butoxycarboyl)-1H-imidazol-4-yl)-2-(3-((tert-butoxycarbonyl)amino)propanamido)propanoicacid

A suspension of (S)-2-(3-aminopropanamido)-3-(1H-imidazol-4-yl)propanoicacid (3.00 g, 13.3 mmol) in a mixture of 1,4-dioxane/water (13.5 mL,2:1) was stirred at ambient temperature until a clear solution wasobtained (˜10 minutes). The mixture was treated dropwise with a solutionof 1 M aqueous NaOH (4.40 mL, 4.42 mmol). The reaction mixture wascooled to 0° C. and treated with di-tert-butyl dicarbonate (2.12 g, 9.72mmol). The ice bath was removed and stirring continued at ambienttemperature for 2 h. After this time, the volatiles were removed underreduced pressure. The residue was diluted with water (40 mL) and ethylacetate (60 mL), acidified to pH ˜3 with 1.0 M potassium bisulfate andextracted with ethyl acetate (3×100 mL). The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure toprovide(S)-3-(1-(tert-butoxycarboyl)-1H-imidazol-4-yl)-2-(3-((tert-butoxycarbonyl)amino)propanamido)propanoicacid (1.70 g, 90%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.15 (s,1H), 7.21 (s, 1H), 6.69-6.67 (br s, 1H), 5.28 (s, 1H), 4.72-4.66 (m,1H), 3.46-3.40 (m, 2H), 3.26 (dd, J=11.7, 5.7 Hz, 1H), 3.13 (dd, J=15.0,6.3 Hz, 1H), 2.46 (t, J=26.3 Hz, 2H), 1.61 (s, 9H), 1.44 (s, 9H), CO₂Hproton not observed.

Preparation of (S)-tert-Butyl4-(2-(3-((tert-butoxycarbonyl)amino)propanamido)-3-((2,5-dioxopyrrolidin-1-yl)oxy)-3-oxopropyl)-1H-Imidazole-1-carboxylate

A solution of(S)-3-(1-(tert-butoxycarboyl)-1H-imidazol-4-yl)-2-(3-((tert-butoxycarbonyl)amino)propanamido)propanoicacid (4.90 g, 11.5 mmol) in tetrahydrofuran (60 mL) was treated withN-hydroxysuccinimide (1.70 g, 14.9 mmol) andN,N′-dicyclohexylcarbodiimide (3.08 g, 14.9 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-tert-butyl4-(2-(3-((tert-butoxycarbonyl)amino)propanamido)-3-((2,5-dioxopyrrolidin-1-yl)oxy)-3-oxopropyl)-1H-imidazole-1-carboxylate(7.20 g, quantitative) as a white foam: ¹H NMR (300 MHz, CDCl₃) δ 8.02(s, 1H), 7.41 (s, 1H), 5.72 (br s, 1H), 5.17-5.11 (m, 1H), 3.51-3.3.41(m, 2H), 3.21 (d, J=4.8 Hz, 2H), 2.82 (m, 5H), 2.49-2.44 (m, 2H), 1.61(s, 9H), 1.42 (s, 9H).

Preparation of tert-Butyl4-((S)-2-(3-((tert-butoxycarbonyl)amino)propanamido)-3-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)-1H-imidazole-1-carboxylate

A suspension of oxycodone (0.500 g, 1.58 mmol) in tetrahydrofuran (8 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (3.20 mL, 3.20mmol). The mixture was stirred at 0° C. for 15 min and then treateddropwise with a solution of (S)-tert-butyl4-(2-(3-((tert-butoxycarbonyl)amino)propanamido)-3-((2,5-dioxopyrrolidin-1-yl)oxy)-3-oxopropyl)-1H-imidazole-1-carboxylate(1.66 g, 3.17 mmol) in tetrahydrofuran (8 mL). The reaction mixture wasstirred at 0° C. for 1 h. After this time, the mixture was poured intosaturated aqueous ammonium chloride (75 mL) and extracted with ethylacetate (2×100 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The cruderesidue was purified by reversed phase chromatography (C18, 10-75%acetonitrile/water) and lyophilized to provide tert-butyl4-((S)-2-(3-((tert-butoxycarbonyl)amino)propanamido)-3-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)-1H-imidazole-1-carboxylate(0.331 g, 29%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.02 (s, 1H),7.38 (s, 1H), 6.70 (d, J=6.6 Hz, 1H), 6.71 (d, J=6.6 Hz, 1H), 6.71 6.62(d, J=8.4 Hz, 1H), 6.02 (br s, 1H), 5.58-5.55 (m, 1H), 4.97-4.90 (m,2H), 3.85 (s, 3H), 3.58-3.38 (m, 2H), 3.20-3.13 (m, 3H), 2.85 (d, J=6.3Hz, 1H), 2.62 (dd, J=18.6, 6.3 Hz, 1H), 2.46-2.40 (m, 3H), 2.38 (s, 3H),2.33-2.21 (m, 2H), 2.16-2.14 (m, 2H), 1.58 (s, 9H), 1.43 (s, 9H).

Preparation of (S)-(4R, 4aS, 7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(3-aminopropanamido)-3-(1H-Imidazo-4-yl)propanoatetris(trifluoroacetic acid salt)

A solution of tert-butyl4-((S)-2-(3-((tert-butoxycarbonyl)amino)propanamido)-3-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)-1H-imidazole-1-carboxylate(100 mg, 0.138 mmol) in methylene chloride (4 mL) was treated withtrifluoroacetic acid (1.5 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was triturated withdiethyl ether then freeze dried from water to provide(S)-(4R, 4aS, 7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(3-aminopropanamido)-3-(1H-imidazo-4-yl)propanoatetris(trifluoroacetic acid salt) (98.6 mg, quantitative) as an off-whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (br s, 1H), 9.01 (s, 1H), 8.85(d, J=7.2 Hz, 1H), 7.77 (br s, 3H), 7.49 (s, 1H), 6.88 (d, J=8.4 Hz,1H), 6.77 (d, J=8.4 Hz, 1H), 6.35 (br s, 1H), 5.53-5.51 (m, 1H), 4.94(s, 1H), 4.69 (q, J=8.1 Hz, 1H), 3.75 (s, 3H), 3.67 (d, J=6.3 Hz, 1H),3.44 (d, J=20.1 Hz, 1H), 3.23-3.09 (m, 4H), 3.00-2.92 (m, 2H), 2.85 (s,3H), 2.70-2.55 (m, 1H), 2.30 (dd, J=18.6, 6.6 Hz, 1H), 2.04 (d, J=17.7Hz, 1H), 1.62 (J=11.4 Hz, 1H), two protons not observed; ESI MS m/z 524[C₂₇H₃₃N₅O₆+H]⁺.

Preparation of(S)-2-((3-((tert-Butoxycarbonyl)amino)propanoyl)oxy)propanoic acid

A solution of 2,5-dioxopyrrolidin-1-yl3-((tert-butoxycarbonyl)amino)propanoate (1.00 g, 3.49 mmol), lacticacid (389 mg, 4.32 mmol), and 4-dimethylaminopyridine (45 mg, 0.37 mmol)in tetrahydrofuran (17 mL) was treated with pyridine (0.34 mL, 4.2 mmol)and heated at 50° C. under a nitrogen atmosphere for 17 h. After thistime, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (50 mL) and washed with aqueous 10% citric acid (2×25 mL) andwater (25 mL). The organic layer was extracted with saturated aqueoussodium bicarbonate (2×25 mL). The combined aqueous bicarbonate layerswere acidified to pH ˜2 with 6 N hydrochloric acid and extracted withethyl acetate (4×25 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoic acid (489mg, 54%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.18 (q, J=7.2Hz, 1H), 5.11 (br s, 1H), 3.49-3.39 (m, 2H), 2.61-2.59 (m, 2H), 1.55 (d,J=7.2 Hz, 3H), 1.44 (s, 9H), CO₂H proton not observed; ESI MS m/z 260[C₁₁H₁₉NO₆−H]⁻.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate

A solution of(S)-2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoic acid (489mg, 1.87 mmol) in tetrahydrofuran (9 mL) was treated withN-hydroxysuccinimide (240 mg, 2.09 mmol) andN,N′-dicyclohexylcarbodiimide (426 mg, 2.06 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide(S)-2,5-dioxopyrrolidin-1-yl2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (773 mg,quantitative) as an off-white foam: ¹H NMR (300 MHz, CDCl₃) δ 5.40 (q,J=6.9 Hz, 1H), 5.16-5.11 (m, 1H), 3.46-3.42 (m, 2H), 2.85 (s, 4H),2.65-2.62 (m, 2H), 1.69 (d, J=6.9 Hz, 3H), 1.43 (s, 9H).

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate

A suspension of oxycodone (560 mg, 1.78 mmol) in tetrahydrofuran (6 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (2.1 mL, 2.1 mmol). Afteraddition was complete, the mixture was stirred in the ice bath for 1 h.The mixture was treated dropwise with a solution of(S)-2,5-dioxopyrrolidin-1-yl2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (761 mg, 2.12mmol) in tetrahydrofuran (6 mL). After addition was complete, themixture was stirred in the ice bath for 15 min. After this time, thereaction mixture was treated with saturated aqueous ammonium chloride(50 mL) and extracted with ethyl acetate (2×50 mL). The combinedorganics were washed with saturated sodium bicarbonate (2×25 mL) andbrine (2×25 mL), dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude residue was purified by columnchromatography (silica gel, 0-10% methanol/methylene chloride) followedby reversed phase column chromatography (50 g C18 column, 10-100%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (132 mg, 13%)as a fluffy white solid: ESI MS m/z 559 [C₂₉H₃₈N₂O₉+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate hydrochloride

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (35 mg, 0.063mmol) in ethyl acetate (1 mL) was treated with a 4.0 M solution ofhydrogen chloride in 1,4-dioxane (1 mL) and stirred under a nitrogenatmosphere at ambient temperature for 1 h. After this time, the reactionmixture was diluted with diethyl ether and sonicated to produce a solidprecipitate. The solid was isolated by filtration, washed with diethylether, dried under vacuum, and freeze-dried from water to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate hydrochloride (27 mg, 81%) as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (br s, 1H), 8.02 (br s,3H), 6.86 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.38 (s, 1H), 5.59(dd, J=6.0, 1.8 Hz, 1H), 5.17 (q, J=7.2 Hz, 1H), 4.99 (s, 1H), 3.76 (s,3H), 3.70 (d, J=6.0 Hz, 1H), 3.43 (d, J=20.1 Hz, 1H), 3.16-3.04 (m, 4H),2.85-2.79 (m, 5H), 2.65-2.57 (m, 1H), 2.49-2.27 (m, 2H, partiallyobscured by solvent peak), 2.05 (apparent d, J=18.0 Hz, 1H), 1.63 (d,J=10.8 Hz, 1H), 1.52 (d, J=7.2 Hz, 3H); ESI MS m/z 459 [C₂₄H₃₀N₂O₇+H]⁺.

Preparation of(S)-2-((3-((tert-Butoxycarbonyl)amino)propanoyl)oxy)-2-phenylacetic acid

A solution of 2,5-dioxopyrrolidin-1-yl3-((tert-butoxycarbonyl)amino)propanoate (1.04 g, 3.62 mmol), mandelicacid (457 mg, 3.00 mmol), and 4-dimethylaminopyridine (29 mg, 0.24 mmol)in tetrahydrofuran (18 mL) was treated with pyridine (0.40 mL, 5.0 mmol)and heated at 50° C. under a nitrogen atmosphere for 48 h. After thistime, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (50 mL) and washed with aqueous 10% citric acid (2×25 mL) andwater (25 mL). The organic layer was extracted with saturated aqueoussodium bicarbonate (2×25 mL). The combined aqueous bicarbonate layerswere acidified to pH ˜2 with 6 N hydrochloric acid and extracted withethyl acetate (4×25 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)-2-phenylacetic acid(791 mg, 81%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.36(m, 5H), 5.99 (s, 1H), 5.18 (br s, 1H), 3.48-3.45 (m, 2H), 2.69-2.62 (m,2H), 1.43 (s, 9H), CO₂H proton not observed.

Preparation of (S)-2-((2,5-Dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate

A solution of(S)-2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)-2-phenylacetic acid(724 mg, 2.24 mmol) in tetrahydrofuran (12 mL) was treated withN-hydroxysuccinimide (298 mg, 2.59 mmol) andN,N′-dicyclohexylcarbodiimide (506 mg, 2.45 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate (1.07 g, quantitative) as anoff-white foam: ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.52 (m, 2H), 7.47-7.40(m, 3H), 6.32 (s, 1H), 5.15 (t, J=5.7 Hz, 1H), 3.48-3.42 (m, 2H), 2.81(s, 4H), 2.72-2.67 (m, 2H), 1.42 (s, 9H).

Preparation of(S)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate

A suspension of oxycodone (645 mg, 2.05 mmol) in tetrahydrofuran (8 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (2.5 mL, 2.5 mmol). Afteraddition was complete, the mixture was stirred in the ice bath for 5 minand at ambient temperature for 5 min. The mixture was re-cooled in anice/brine bath and treated dropwise with a solution of(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate (1.04 g, 2.47 mmol) intetrahydrofuran (8 mL). After addition was complete, the mixture wasstirred in the ice/brine bath for 45 min. After this time, the reactionmixture was treated with saturated aqueous ammonium chloride (50 mL) andextracted with ethyl acetate (2×50 mL). The combined organics werewashed with saturated sodium bicarbonate (50 mL) and brine (50 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by column chromatography(silica gel, 0-10% methanol/methylene chloride) followed by reversedphase column chromatography (50 g C18 column, 30-100%acetonitrile/water) and freeze dried to provide(S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate (128 mg, 10%) as a fluffy whitesolid: ESI MS m/z 621 [C₃₄H₄₀N₂O₉+H]⁺.

Preparation of(S)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-aminopropanoate dihydrochloride

A solution of(S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate (87 mg, 0.14 mmol) in ethylacetate (1 mL) was treated with a 4.0 M solution of hydrogen chloride in1,4-dioxane (1 mL) and stirred under a nitrogen atmosphere at ambienttemperature for 1.5 h. After this time, the reaction mixture was dilutedwith diethyl ether and sonicated to produce a solid precipitate. Thesolid was isolated by filtration, washed with diethyl ether, dried undervacuum, and freeze-dried from acetonitrile/water to provide(S)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-aminopropanoate dihydrochloride (51 mg, 61%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆, Mixture of diastereomers) δ 9.22 (br s, 1H), 8.03 (brs, 3H), 7.57-7.56 (m, 2H), 7.49-7.46 (m, 3H), 6.86-6.80 (m, 1H),6.76-6.72 (m, 1H), 6.38 (s, 1H), 6.14 (s, 0.66H), 6.13 (s, 0.34H), 5.55(dd, J=6.3, 2.1 Hz, 0.66H), 5.47 (dd, J=6.0, 1.8 Hz, 0.34H), 4.96 (s,0.66H), 4.93 (s, 0.34H), 3.72 (s, 1.02H), 3.70-3.68 (m, 1H), 3.64 (s,1.98H), 3.41 (d, J=20.1 Hz, 1H), 3.14-3.07 (m, 4H), 2.89-2.83 (m, 5H),2.63-2.59 (m, 1H), 2.49-2.27 (m, 2H, partially obscured by solventpeak), 2.04 (apparent d, J=18.3 Hz, 1H), 1.61 (d, J=11.7 Hz, 1H); ESI MSm/z 521 [C₂₉H₃₂N₂O₇+H]⁺; HPLC (Method A) 95.0% (AUC), t_(R)=7.95 min.

Preparation of(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((tert-butoxycarbonyl)amino)propanoate

A suspension of oxycodone (1.02 g, 3.23 mmol) in tetrahydrofuran (10 mL)was cooled in an ice bath and treated with a 1.0 M solution of potassiumtert-butoxide in tetrahydrofuran (3.55 mL, 3.55 mmol). After additionwas complete, the mixture was stirred under nitrogen atmosphere in theice bath for 45 min and at ambient temperature for 20 min. The solutionwas re-cooled in an ice/brine bath, treated dropwise with a solution of2,5-dioxopyrrolidin-1-yl 3-((tert-butoxycarbonyl)amino)propanoate (0.972g, 3.39 mmol) in tetrahydrofuran (10 mL), and stirred for 2 h. Afterthis time, the reaction mixture was treated with saturated aqueousammonium chloride (75 mL) and extracted with ethyl acetate (3×100 mL).The combined organics were washed with saturated aqueous ammoniumchloride (100 mL), saturated sodium bicarbonate (2×100 mL), and brine(2×100 mL); dried over sodium sulfate; filtered; and concentrated underreduced pressure to provide(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((tert-butoxycarbonyl)amino)propanoate (1.20 g, 76%) as a yellow oil:ESI MS m/z 487 [C₂₆H₃₄N₂O₇+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-aminopropanoate dihydrochloride

A solution of(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((tert-butoxycarbonyl)amino)propanoate (0.500 g, 1.06 mmol) in1,4-dioxane (1 mL) was treated with 4 N hydrogen chloride in 1,4-dioxane(5 mL) at ambient temperature and stirred for 2 h. After this time, theresulting precipitate was isolated by filtration, washed with1,4-dioxane (15 mL), and dried under vacuum to provide(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-aminopropanoate dihydrochloride (0.560 g, quantitative) as anoff-white solid: ESI MS m/z 387 [C₂₁H₂₆N₂O₅+H].

Preparation of(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate

A mixture of(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-aminopropanoate dihydrochloride (0.500 g, 1.09 mmol),(S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (0.570 g, 1.63 mmol), andN,N-diisopropylethylamine (0.95 mL, 5.4 mmol) in methylene chloride (10mL) was stirred at ambient temperature for 1 h. After this time, thereaction mixture was concentrated under reduced pressure. The cruderesidue was purified by column chromatography (silica gel, 0-4%methanol/methylene chloride) to provide(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate (0.360g, 53%) as a light yellow oil: ESI MS m/z 621 [C₃₄H₄₀N₂O₉+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-hydroxy-2-phenylacetamido)propanoate trifluoroacetic acid salt

A solution of(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate (0.100g, 0.161 mmol) in methylene chloride (3 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The crude residue was purified byreversed phase column chromatography (50 g C18 column, 5-50%acetonitrile/water) and freeze dried to provide(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-hydroxy-2-phenylacetamido)propanoate trifluoroacetic acid salt(0.026 g, 32%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.13 (t,J=6.0 Hz, 1H), 7.42-7.24 (m, 7H), 6.83 (d, J=8.1 Hz, 1H), 6.72 (d, J=8.1Hz, 1H), 6.20 (d, J=4.8 Hz, 1H), 5.47-5.45 (m, 1H), 4.93 (s, 1H), 4.89(d, J=4.8 Hz, 1H), 3.74 (s, 3H), 3.41-3.28 (m, 2H), 3.10-2.80 (m, 2H),2.78-2.60 (m, 5H), 2.46-2.33 (m, 2H), 2.30-2.12 (m, 1H), 2.02 (d, J=18.0Hz, 1H), 1.60-1.50 (m, 1H), one proton not observed; ESI MS m/z 521[C₂₉H₃₂N₂O₇+H]⁺; HPLC (Method A) 91.8% (AUC), t_(R)=8.15 min.

Preparation of(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate

A mixture of (4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-aminopropanoate dihydrochloride (0.500 g, 1.09 mmol),(S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)oxy)propanoate(0.469 g, 1.63 mmol) and N,N-diisopropylethylamine (0.95 mL, 5.44 mmol)in methylene chloride (10 mL) was stirred at ambient temperature for 2h. After this time, the reaction mixture was concentrated under reducedpressure. The crude residue was purified by column chromatography(silica gel, 0-4% methanol/methylene chloride) to provide(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate (0.260 g, 43%)as a white foam: ESI MS m/z 559 [C₂₉H₃₈N₂O₉+H]⁺;

Preparation of(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-hydroxypropanamido)propanoate trifluoroacetic acid salt

A solution of(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate (0.080 g,0.143 mmol) in methylene chloride (3 mL) was treated withtrifluoroacetic acid (1.5 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was triturated with amixture of methylene chloride/diethyl ether (1:1) and filtered to give(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-hydroxypropanamido)propanoatetrifluoroacetic acid salt (0.044mg, 67%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (br s, 1H),8.09 (d, J=6.9 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H),6.28 (s, 1H), 5.53-5.50 (m, 1H), 5.00 (s, 1H), 4.39-4.34 (m, 1H),4.03-3.99 (m, 1H), 3.75 (s, 3H), 3.64 (d, J=5.7 Hz, 1H), 3.50-3.35 (m,2H), 3.13-3.06 (m, 2H), 2.84 (d, J=4.5 Hz, 3H), 2.75-2.55 (m, 1H),2.32-2.24 (m, 1H), 2.06 (d, J=18.0 Hz, 1H), 1.59 (d, J=11.7 Hz, 1H),1.40 (d, J=7.2 Hz, 3H), 1.22 (d, J=10.5 Hz, 3H); ESI MS m/z 459[C₂₄H₃₀N₂O₇+H]⁺; HPLC (Method A) 93.9% (AUC), t_(R)=7.41 min.

Preparation of(S)-2-(2-((S)-2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylaceticacid

A solution of (S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (2.01 g, 7.41 mmol),mandelic acid (1.35 g, 8.87 mmol), and 4-dimethylaminopyridine (100 mg,0.819 mmol) in tetrahydrofuran (30 mL) was treated with pyridine (0.70mL, 8.7 mmol) and heated at 50° C. under a nitrogen atmosphere for 16 h.After this time, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (50 mL) and washed with aqueous 10% citric acid (2×25 mL) andwater (25 mL). The organic layer was extracted with saturated aqueoussodium bicarbonate (2×25 mL). The combined aqueous bicarbonate layerswere acidified to pH ˜2 with 6 N hydrochloric acid and extracted withethyl acetate (4×25 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to providecrude(S)-2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylaceticacid (1.55 g, 68%) as a white semisolid. The material was recrystallizedfrom diethyl ether/ethyl acetate/heptanes to give the product (258 mg)as a white crystalline solid: ¹H NMR (300 MHz, CDCl₃) δ 7.49-7.45 (m,2H), 7.42-7.40 (m, 3H), 6.00 (s, 1H), 4.76 (dd, J=6.3, 3.6 Hz, 1H), 3.14(dd, J=17.1, 3.6 Hz, 1H), 2.93 (dd, J=17.1, 6.3 Hz, 1H), 1.55 (s, 6H),CO₂H proton not observed; ESI MS m/z 615 [(2×C₁₅H₁₆O₇)−H]⁻.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate

A solution of(S)-2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylaceticacid (258 mg, 0.836 mmol) in tetrahydrofuran (4 mL) was treated withN-hydroxysuccinimide (107 mg, 0.930 mmol) andN,N′-dicyclohexylcarbodiimide (191 mg, 0.926 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide(S)-2,5-dioxopyrrolidin-1-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate(372 mg, quantitative) as an off-white foam: ¹H NMR (300 MHz, CDCl₃) δ7.55-7.52 (m, 2H), 7.46-7.44 (m, 3H), 6.38 (s, 1H), 4.77 (dd, J=6.6, 3.6Hz, 1H), 3.14 (dd, J=17.4, 3.6 Hz, 1H), 2.92 (dd, J=17.4, 6.6 Hz, 1H),2.81 (s, 4H), 1.57 (s, 3H), 1.56 (s, 3H).

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(2-((S)-2,2-d methyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate

A suspension of oxycodone (241 mg, 0.764 mmol) in tetrahydrofuran (4 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (0.92 mL, 0.92 mmol). Afteraddition was complete, the mixture was stirred in the ice bath for 10min and at ambient temperature for 5 min. The mixture was re-cooled inan ice/brine bath and treated dropwise with a solution of(S)-2,5-dioxopyrrolidin-1-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate(370 mg, 0.913 mmol) in tetrahydrofuran (4 mL). After addition wascomplete, the mixture was stirred in the ice bath for 40 min. After thistime, the reaction mixture was treated with saturated aqueous ammoniumchloride (25 mL) and extracted with ethyl acetate (2×25 mL). Thecombined organics were washed with saturated sodium bicarbonate (25 mL)and brine (25 mL), dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude residue was purified by columnchromatography (silica gel, 0-10% methanol/methylene chloride) followedby reversed phase column chromatography (15.5 g C18 column, 30-100%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate(49 mg, 11%) as a fluffy white solid: ESI MS m/z 606 [C₃₃H₃₅NO₁₀+H]⁺.

Preparation of(S)-2-Hydroxy-4-((S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid hydrochloride

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate(47 mg, 0.078 mmol) in 1,4-dioxane (4 mL) was treated with a 4.0 Msolution of hydrogen chloride in 1,4-dioxane (0.5 mL) followed by water(4 drops) and stirred under a nitrogen atmosphere at ambient temperaturefor 15 min. After this time, the reaction mixture was partiallyconcentrated under reduced pressure, diluted with acetonitrile andwater, and freeze dried. The crude product was purified by reversedphase column chromatography (15.5 g C18 column, 5-80%acetonitrile/water) and freeze dried to provide(S)-2-hydroxy-4-((S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid hydrochloride (28 mg, 60%) as a white solid: ¹H NMR (300 MHz,DMSO-d₆, Mixture of diastereomers) δ 7.56-7.54 (m, 2H), 7.46-7.44 (m,3H), 6.75-6.62 (m, 1H), 6.09 (s, 0.68H), 6.05 (s, 0.32H), 5.54 (dd,J=5.4, 2.4 Hz, 0.68H), 5.42 (dd, J=5.4, 2.4 Hz, 0.32H), 4.81 (s, 1H),4.29-4.25 (m, 1H), 3.70 (s, 0.96H), 3.61 (s, 2.04H), 3.13 (d, J=18.9 Hz,1H), 2.93-2.83 (m, 2H), 2.73-2.59 (m, 2H), 2.49-2.40 (m, 1H, partiallyobscured by solvent peak), 2.38 (s, 3H), 2.31-1.95 (m, 5H), 1.39 (d,J=10.8 Hz, 1H), CO₂H, HCl, and two OH protons not observed; ESI MS m/z566 [C₃₀H₃₁NO₁₀+H]⁺; HPLC (Method A) 95.5% (AUC), t_(R)=8.86 min.

Preparation of(S)-2-((S)-5-(tert-Butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoicacid

A solution of (S)-5-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (3.01 g, 7.52 mmol), lacticacid (678 mg, 7.53 mmol), and 4-dimethylaminopyridine (93 mg, 0.76 mmol)in tetrahydrofuran (40 mL) was treated with pyridine (0.61 mL, 7.6 mmol)and heated at 50° C. under a nitrogen atmosphere for 48 h. After thistime, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (100 mL) and washed with aqueous 10% citric acid (2×50 mL) andwater (50 mL). The organic layer was extracted with saturated aqueoussodium bicarbonate (2×50 mL). The combined aqueous bicarbonate layerswere acidified to pH ˜1 with 6 N hydrochloric acid and extracted withethyl acetate (4×50 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-2-(((S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoicacid (2.49 g, 88%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ5.24-5.14 (m, 2H), 4.35-4.32 (m, 1H), 2.43-2.37 (m, 2H), 2.26-2.15 (m,1H), 2.03-1.93 (m, 1H), 1.56 (d, J=7.2 Hz, 3H), 1.45 (s, 9H), 1.44 (s,9H), CO₂H proton not observed.

Preparation of (S)-5-tert-Butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate

A solution of(S)-2-(((S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoicacid (2.47 mg, 6.59 mmol) in tetrahydrofuran (33 mL) was treated withN-hydroxysuccinimide (836 mg, 7.26 mmol) andN,N′-dicyclohexylcarbodiimide (1.51 mg, 7.32 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide (S)-5-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate 3.36 g, quantitative) as atan foam: ¹H NMR (300 MHz, CDCl₃) δ 5.45 (q, J=6.9 Hz, 1H), 5.20-5.12(m, 1H), 4.43-4.33 (m, 1H), 2.84 (s, 4H), 2.39-2.34 (m, 2H), 2.0-2.15(m, 1H), 2.02-1.90 (m, 1H), 1.71 (d, J=6.9 Hz, 3H), 1.44 (s, 9H), 1.43(s, 9H).

Preparation of (S)-5-tert-Butyl1-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate

A suspension of oxycodone (705 mg, 2.24 mmol) in tetrahydrofuran (9 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (2.7 mL, 2.7 mmol). Afteraddition was complete, the mixture was stirred in the ice bath for 5 minand at ambient temperature for 5 min. The mixture was re-cooled in anice/brine bath and treated dropwise with a solution of (S)-5-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (1.28 g, 2.71 mmol) intetrahydrofuran (9 mL). After addition was complete, the mixture wasstirred in the ice/brine bath for 45 min. After this time, the reactionmixture was treated with saturated aqueous ammonium chloride (50 mL) andextracted with ethyl acetate (2×50 mL). The combined organics werewashed with saturated sodium bicarbonate (2×25 mL) and brine (25 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by column chromatography(silica gel, 0-10% methanol/methylene chloride) followed by reversedphase column chromatography (150 g C18 column, 20-100%acetonitrile/water) and freeze dried to provide (S)-5-tert-butyl1-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (219 mg, 15%) as a fluffywhite solid: ESI MS m/z 673 [C₃₅H₄₈N₂O₁₁+H]⁺.

Preparation of(S)-4-Amino-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid hydrochloride

A solution of (S)-5-tert-butyl1-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (145 mg, 0.216 mmol) inethyl acetate (2 mL) was treated with a 4.0 M solution of hydrogenchloride in 1,4-dioxane (2 mL) and stirred under a nitrogen atmosphereat ambient temperature for 2 h. After this time, the reaction mixturewas diluted with diethyl ether and sonicated to produce a solidprecipitate. The solid was isolated by filtration, washed with diethylether, dried under vacuum, and freeze-dried from acetonitrile/water toprovide(S)-4-amino-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid hydrochloride (48 mg, 38%) as a white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 9.09 (br s, 1H), 8.52 (br s, 2H), 6.86 (d, J=8.4 Hz, 1H),6.76 (d, J=8.1 Hz, 1H), 6.31 (br s, 1H), 5.63-5.60 (m, 1H), 5.35 (q,J=6.9 Hz, 1H), 5.02 (s, 1H), 4.20 (apparent t, J=6.6 Hz, 1H), 3.75 (s,3H), 3.65 (br s, 1H), 3.43 (d, J=19.8 Hz, 1H, partially obscured bywater peak), 3.14-3.05 (m, 2H), 2.83 (s, 3H), 2.62-2.56 (m, 1H),2.49-2.27 (m, 3H, partially obscured by solvent peak), 2.10-2.04 (m,3H), 1.65-1.58 (m, 1H), 1.57 (d, J=7.2 Hz, 3H), CO₂H proton notobserved, one proton obscured by solvent peaks; ESI MS m/z 517[C₂₆H₃₂N₂O₉+H]⁺; HPLC (Method A) 97.0% (AUC), t_(R)=6.88 min.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate

A mixture of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-aminopropanoate (190 g, 0.309 mmol), (S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (0.106 g, 0.392 mmol)and pyridine (0.08 mL, 1 mmol) in methylene chloride (4 mL) was stirredat ambient temperature for 3 h. After this time, the reaction wasconcentrated under reduced pressure and purified by columnchromatography (silica gel, 0-20% methanol/methylene chloride) toprovide(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate(0.050 g, 30%) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 9.17 (br s,1H), 8.60 (d, J=6.6 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz,1H), 6.28 (s, 1H), 5.52-51 (m, 1H), 4.98 (s, 1H), 4.83-4.80 (m, 1H),4.35-4.31 (m, 1H), 3.76 (s, 3H), 3.65-3.63 (m, 1H), 3.42 (d, J=19.5 Hz,1H), 3.16-3.07 (m, 2H), 2.85-2.84 (m, 3H), 2.75-2.55 (m, 3H), 2.30-2.24(m, 1H), 2.06 (d, J=17.4 Hz, 1H), 1.64 (d, J=12.3 Hz, 1H), 1.50 (s, 6H),1.37 (d, J=7.2 Hz, 3H).

Preparation of(S)-2-hydroxy-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)amino)-4-oxobutanoicacid hydrochloride

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate(0.040 g, 0.074 mmol) in 1,4-dioxane (4 mL) was treated with 4 Nhydrogen chloride in 1,4-dioxane (0.5 mL) and 4 drops of water. Thereaction mixture was stirred at ambient temperature for 0.5 h. Afterthis time, the reaction mixture was concentrated under reduced pressure.The residue was triturated with diethyl ether and freeze dried fromwater toprovide(S)-2-hydroxy-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)amino)-4-oxobutanoicacid hydrochloride (40 mg, quantitative) as an off-white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 12.5 (br s, 1H), 9.21 (br s, 1H), 8.45 (d, J=6.3Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.34 (s, 1H),5.54-5.52 (m, 1H), 4.99 (s, 1H), 4.37-4.31 (m, 2H), 3.75 (s, 3H),3.69-3.65 (m, 2H), 3.39 (s, 3H), 3.13-3.07 (m, 2H), 2.84 (d, J=4.5 Hz,3H), 2.28 (d, J=6.3 Hz, 1H), 2.05 (d, J=17.7 Hz, 1H), 1.63 (d, J=11.1Hz, 1H), 1.36 (d, J=7.5 Hz, 3H), 1.25 (d, J=7.5 Hz, 1H); ESI MS m/z 503[C₂₅H₃₀N₂O₉+H]⁺; HPLC (Method A) 92.3% (AUC), t_(R)=7.03 min.

Preparation of(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((R)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate

A solution of(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-aminopropanoate dihydrochloride (0.245 g, 0.533 mmol),(R)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (0.279, 0.800 mmol), andN,N-diisopropylethylamine (0.46 mL, 2.7 mmol) in methylene chloride (5mL) was stirred at ambient temperature for 2 h. After this time, thereaction was concentrated under reduced pressure. The crude residue wasdiluted with ethyl acetate (3×75 mL) and washed with water. The combinedorganics were dried over sodium sulfate, filtered, and concentratedunder reduced pressure to give(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((R)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate (0.095g, 29%) as a colorless oil: ESI MS m/z 621 [C₃₄H₄₀N₂O₉+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((R)-2-hydroxy-2-phenylacetamido)propanoatetrifluoroacetic acid salt

A solution of(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((R)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate (0.065g, 0.105 mmol) in dichloromethane (2 mL) was treated withtrifluoroacetaic acid (0.6 mL) and stirred at ambient temperature for 1h. After this time, the reaction mixture was concentrated under reducedpressure. The crude residue was purified by reversed phase columnchromatography (50 g C18 column, 5-25% acetonitrile/water) and freezedried to provide(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((R)-2-hydroxy-2-phenylacetamido)propanoatetrifluoroacetic acid salt(0.015 mg, 27%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.16(br s, 1H), 8.13 (t, J=6.3 Hz, 1H), 7.34-7.31 (m, 2H), 7.29-7.23 (m,3H), 6.86 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.26 (s, 1H), 6.21(d, J=4.5 Hz, 1H), 5.50-5.48 (m, 1H), 4.97 (s, 1H), 4.89 (d, J=4.2 Hz,1H), 3.75 (m, 3H), 3.64-3.63 (m, 1H), 3.46-3.33 (m, 3H), 3.15-3.06 (m,2H), 2.84 (d, J=4.5 Hz, 3H), 2.63 (t, J=6.9 Hz, 3H), 2.28-2.22 (m, 1H),2.05 (d, J=17.7H, 1H), 1.63 (d, J=12.9 Hz, 1H); ESI MS m/z 521[C₂₉H₃₂N₂O₇+H]⁺; HPLC (Method A) >99% (AUC), t_(R)=8.16 min.

Preparation of(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate

A solution of(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-aminopropanoate dihydrochloride (0.550 g, 1.19 mmol),(S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (0.487 g, 1.79 mmol),and N,N-diisopropylethylamine (1.0 mL, 6.0 mmol) in methylene chloride(10 mL) was stirred at ambient temperature for 2 h. After this time, thereaction was concentrated under reduced pressure. The crude residue waspurified by column chromatography (silica gel, 0-4% methanol/methylenechloride) to provide(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate(0.240 g, 37%) as a colorless oil: ESI MS m/z 543 [C₂₈H₃₄N₂O₉+H]⁺.

Preparation of(S)-2-Hydroxy-4-((3-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)amino)-4-oxobutanoicacid

A solution of(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate(0.115 g, 0.212 mmol) in 1,4-dioxane (4 mL) was treated with 4 Nhydrogen chloride in 1,4-dioxane (0.4 mL) and 4 drops of water. Thereaction mixture was stirred at ambient temperature for 1 h. Additional4 N hydrogen chloride in 1,4-dioxane (0.25 mL) and water (2 drops) wereadded and stirring was continued for another 1 h. After this time, thereaction mixture was concentrated under reduced pressure. The cruderesidue was triturated with diethyl ether, filtered, and purified byreversed phase column chromatography (50 g C18 column, 5-15%acetonitrile/water) and freeze dried toprovide(S)-2-hydroxy-4-((3-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)amino)-4-oxobutanoicacid (0.038 mg, 36%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ8.05 (t, J=5.4H, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.66 (d, J=8.1 Hz, 1H),5.55-5.52 (m, 1H), 4.87 (s, 1H), 4.24-4.20 (m, 1H), 3.73 (s, 3H), 3.14(d, J=18.9 Hz, 2H), 2.91 (d, J=6.0 Hz, 1H), 2.73-2.55 (m, 3H), 2.48-2.42(m, 2H), 2.39-2.20 (m, 5H), 2.17-1.90 (m, 3H), 1.40 (d, J=11.1 Hz, 1H),CO₂H and two OH protons not observed, one proton obscured by solventpeaks; ESI MS m/z 503 [C₂₅H₃₀N₂O₉+H]⁺; HPLC (Method A) 98.9% (AUC),t_(R)=7.06 min.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate

A mixture of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-aminopropanoate dihydrochloride (0.500 g, 1.09 mmol),(S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (0.571 g, 1.63 mmol), andN,N-diisopropylethylamine (0.95 mL, 5.4 mmol) in methylene chloride (10mL) was stirred at ambient temperature for 1 h. After this time, thereaction mixture was concentrated under reduced pressure. The cruderesidue was purified by column chromatography (silica gel, 0-4%methanol/methylene chloride) toprovide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate, (0.567g, 84%) as a light yellow oil: ESI MS m/z 621 [C₃₄H₄₀N₂O₉+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-hydroxy-2-phenylacetamido)propanoatetrifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate (0.110g, 0.177 mmol) in methylene chloride (3 mL) was treated withtrifluoroacetic acid (1 mL) and stirred at ambient temperature for 1 h.After this time, the reaction mixture was concentrated under reducedpressure. The crude residue was purified by reversed phase columnchromatography (50 g C18 column, 5-25% acetonitrile/water) and freezedried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-hydroxy-2-phenylacetamido)propanoatetrifluoroacetic acid salt(0.020 mg, 22%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (brs, 1H), 8.43 (d, J=6.9 Hz, 1H), 7.43-7.40 (m, 2H), 7.34-7.21 (m, 3H),6.85 (d, J=8.1 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.27-6.22 (m, 2H),5.41-5.40 (m, 1H), 4.96 (d, J=4.8 Hz, 2H), 4.40-4.35 (m, 1H), 3.75 (s,3H), 3.70-3.55 (m, 1H), 3.50-3.35 (m, 1H), 3.20-3.00 (m, 2H), 2.83 (s,3H), 2.27-2.22 (m, 1H), 2.05-1.99 (m, 1H), 1.65-1.61 (m, 1H), 1.40 (d,J=7.2 Hz, 3H), one proton obscured by solvent peaks; ESI MS m/z 521[C₂₉H₃₂N₂O₇+H]⁺; HPLC (Method A) 94.2% (AUC), t_(R)=8.58 min.

Preparation of(S)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate

A suspension(S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-aminopropanoate dihydrochloride (50 mg, 0.084 mmol) and(S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)oxy)propanoate (36mg, 0.13 mmol) in methylene chloride (2 mL) was treated withN,N-diisopropylethylamine (0.06 mL, 0.3 mmol) and stirred under anitrogen atmosphere for 30 min. After this time, the reaction mixturewas diluted with methylene chloride (10 mL) and washed with saturatedaqueous ammonium chloride (10 mL). The organic layer was dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (15.5g C18 column, 20-100% acetonitrile/water) and freeze dried to provide(S)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate (30 mg, 51%)as a fluffy white solid: ESI MS m/z 693 [C₃₇H₄₄N₂O₁₁+H]⁺.

Preparation of(S)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((S)-2-hydroxypropanamido)propanoate trifluoroacetic acid salt

A solution of(S)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate (30 mg, 0.043mmol) in methylene chloride (1 mL) was treated with trifluoroacetic acid(0.5 mL) and stirred under a nitrogen atmosphere at ambient temperaturefor 30 min. After this time, the reaction mixture concentrated underreduced pressure. The residue was treated with diethyl ether (5 mL) andsonicated to produce a solid precipitate. The solid was isolated byfiltration, washed with diethyl ether, dried under vacuum, andfreeze-dried from acetonitrile/water. The crude product was purified byreversed phase column chromatography (15.5 g C18 column, 10-80%acetonitrile/water) and freeze dried to provide(S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((S)-2-hydroxypropanamido)propanoate trifluoroacetic acid salt (23 mg,77%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆, Mixture ofdiastereomers) δ 9.17 (br s, 1H), 7.82-7.79 (m, 1H), 7.57-7.54 (m, 2H),7.47-7.45 (m, 3H), 6.86-6.80 (m, 1H), 6.74-6.71 (m, 1H), 6.30 (s, 1H),6.09 (s, 0.64H), 6.07 (s, 0.36H), 5.56-5.46 (m, 2H), 4.96 (s, 0.64H),4.93 (s, 0.36H), 3.98-3.90 (m, 1H), 3.71 (s, 1.08H), 3.63 (s, 1.92H),3.62 (br s, 1H), 3.46-3.32 (m, 3H, partially obscured by water peak),3.14-3.05 (m, 2H), 2.83 (s, 3H), 2.65-2.61 (m, 2H), 2.49-2.39 (m, 2H,partially obscured by solvent peak), 2.30-2.24 (m, 1H), 2.09-2.03 (m,1H), 1.65-1.61 (m, 1H), 1.19-1.16 (m, 3H); ESI MS m/z 593[C₃₂H₃₆N₂O₉+H]⁺; HPLC (Method A) 98.2% (AUC), t_(R)=8.89 min.

Preparation of(6S,13S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl13-((1H-imidazol-4-yl)methyl)-2,2,6-trimethyl-4,7,11-trioxo-3,5-dioxa-8,12-diazatetradecan-14-oate

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(3-aminopropanamido)-3-(1H-imidazol-4-yl)propanoatetrifluoroaceticacid salt (0.220 g, 0.250 mmol), (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate (0.088 g, 0.31 mmol) andN,N-diisopropylethylamine (0.22 mL, 1.3 mmol) in methylene chloride (5mL) was stirred at ambient temperature for 2 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas diluted in ethyl acetate (100 mL) and successively washed with water(75 mL) and brine (75 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The cruderesidue was purified by column chromatography (silica gel, 0-20%methanol/methylene chloride) to provide(6S,13S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl13-((1H-imidazol-4-yl)methyl)-2,2,6-trimethyl-4,7,11-trioxo-3,5-dioxa-8,12-diazatetradecan-14-oate(0.045 g, 26%) as a light yellow foam: ESI MS m/z 696 [C₃₅H₄₅N₅O₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(3-((S)-2-hydroxypropanamido)propanamido)-3-(1H-imidazol-4-yl)propanoatebis(trifluoroacetic acid salt)

A solution of(6S,13S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl13-((1H-imidazol-4-yl)methyl)-2,2,6-trimethyl-4,7,11-trioxo-3,5-dioxa-8,12-diazatetradecan-14-oate(0.045 mg, 0.065 mmol) in methylene chloride (4 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The crude residue was purified byreversed phase column chromatography (50 g C18 column, 5-60%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(3-((S)-2-hydroxypropanamido)propanamido)-3-(1H-imidazol-4-yl)propanoatebis(trifluoroaceticacid salt) (99 mg, quantitative) as a white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 9.19 (br s, 1H), 8.94 (s, 1H), 8.59 (d, J=7.5 Hz, 1H), 7.72(t, J=7.2 Hz, 1H), 7.45 (s, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.1Hz, 1H), 6.29 (s, 1H), 5.53-5.51 (m, 2H), 4.96 (s, 1H), 4.68-4.65 (m,1H), 3.98-3.88 (m, 1H), 3.75 (s, 3H), 3.60-3.70 (m, 1H), 3.25-3.23 (m,3H), 3.15-3.10 (m, 4H), 2.85 (s, 3H), 2.33-2.28 (m, 3H), 2.07-2.02 (m,1H), 1.63 (d, J=11.1 Hz, 1H), 1.228-1.24 (m, 2H), 1.17 (d, J=6.9 Hz,3H); ESI MS m/z 596 [C₃₀H₃₇N₅O₈+H]⁺.

Preparation of(S)-4-((S)-2-((tert-Butoxycarbonyl)oxy)propanamido)-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid

A suspension of(S)-4-amino-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid dihydrochloride (85 mg, 0.14 mmol) and (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate (67 mg, 0.23 mmol) in methylenechloride (3 mL) was treated with N,N-diisopropylethylamine (0.10 mL,0.57 mmol) and stirred under a nitrogen atmosphere for 30 min. Afterthis time, the reaction mixture was diluted with methylene chloride (10mL) and washed with saturated aqueous ammonium chloride (10 mL). Theorganic layer was dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude residue was purified by reversed phasecolumn chromatography (15.5 g C18 column, 20-100% acetonitrile/water)and freeze dried to provide to provide(S)-4-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid (58 mg, 58%) as a fluffy white solid: ESI MS m/z 689[C₃₄H₄₄N₂O₁₃+H]⁺.

Preparation of(S)-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-((S)-2-hydroxypropanamido)-5-oxopentanoicacid trifluoroacetic acid salt

A solution of(S)-4-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid (54 mg, 0.078 mmol) in methylene chloride (1 mL) was treated withtrifluoroacetic acid (0.5 mL) and stirred under a nitrogen atmosphere atambient temperature for 45 min. After this time, the reaction mixtureconcentrated under reduced pressure. The residue was treated withdiethyl ether (5 mL) and sonicated to produce a solid precipitate. Thesolid was isolated by filtration, washed with diethyl ether, dried undervacuum, and freeze-dried from acetonitrile/water to provide(S)-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-((S)-2-hydroxypropanamido)-5-oxopentanoicacid trifluoroacetic acid salt (44 mg, 81%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 12.19 (br s, 1H), 9.17 (br s, 1H), 7.99 (d, J=7.8Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.30 (s, 1H),5.60 (dd, J=6.0, 2.1 Hz, 1H), 5.54 (br s, 1H), 5.16 (q, J=6.9 Hz, 1H),5.01 (s, 1H), 4.42-4.34 (m, 1H), 4.01 (q, J=6.9 Hz, 1H), 3.75 (s, 3H),3.65 (d, J=6.3 Hz, 1H), 3.43 (d, J=20.1 Hz, 1H, partially obscured bywater peak), 3.16-3.07 (m, 2H), 2.84 (apparent d, J=4.8 Hz, 3H),2.66-2.57 (m, 1H), 2.49-2.43 (m, 1H, partially obscured by solventpeak), 2.37-2.23 (m, 3H), 2.15-2.05 (m, 2H), 1.97-1.85 (m, 1H), 1.64 (d,J=10.8 Hz, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.22 (d, J=6.9 Hz, 3H); ESI MSm/z 589 [C₂₉H₃₆N₂O₁₁+H]⁺; HPLC (Method A) 95.0% (AUC), t_(R)=7.63 min.

Preparation of(4R,4aS,7aR,12bS)-9-Methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((tert-butoxycarbonyl)amino)propanoate)

A suspension of oxycodone (0.490 g, 1.55 mmol) in tetrahydrofuran (10mL) was cooled in an ice bath and treated with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (3.1 mL, 3.1 mmol).After addition was complete, the mixture was stirred under nitrogenatmosphere in the ice bath for 45 min and at ambient temperature for 20min. The solution was re-cooled in an ice/brine bath, treated dropwisewith a solution of 2,5-dioxopyrrolidin-1-yl3-((tert-butoxycarbonyl)amino)propanoate (0.890 g, 3.11 mmol) intetrahydrofuran (5 mL), and stirred for 2 h. After this time, thereaction mixture was treated with saturated aqueous ammonium chloride(75 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganics were washed with saturated aqueous ammonium chloride (100 mL),saturated sodium bicarbonate (2×100 mL), and brine (2×100 mL); driedover sodium sulfate; filtered; and concentrated under reduced pressureto provide(4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((tert-butoxycarbonyl)amino)propanoate) (0.990 g, 97%) as a yellowoil: ESI MS m/z 658 [C₃₄H₄₇N₃O₁₀+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-9-Methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-aminopropanoate) tris(trifluoroacetic acid salt)

A solution of(4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((tert-butoxycarbonyl)amino)propanoate) (0.990 g, 1.51 mmol) inmethylene chloride (20 mL) was treated with trifluoroacetic acid (10 mL)and stirred under a nitrogen atmosphere at ambient temperature for 1 h.After this time, the reaction mixture was concentrated under reducedpressure and dried under vacuum to provide(4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-aminopropanoate) tris(trifluoroacetic acid salt) (1.50 g,quantitative) as a yellow oil: ESI MS m/z 458 [C₂₄H₃₁N₃O₆+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-Methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate)

A mixture of(4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-aminopropanoate) tris(trifluoroacetic acid salt)(0.580 g, 0.725mmol), (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate (0.521 g, 1.81 mmol) andN,N-diisopropylethylamine (0.63 mL, 3.6 mmol) in methylene chloride (10mL) was stirred at ambient temperature for 2 h. After this time, thereaction was concentrated under reduced pressure. The crude residue waspurified by column chromatography (silica gel, 0-6% methanol/methylenechloride) to provide(S)-(4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate) (0.300 g,52%) as a colorless oil: ESI MS m/z 802 [C₄₀H₅₅N₃O₁₄+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-Methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-hydroxypropanamido)propanoate) trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate) (0.300 g,0.374 mmol) in methylene chloride (5 mL) was treated withtrifluoroacetic acid (2 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The crude residue was purified byreverse phase chromatography (50 g C18 column, 5-25% acetonitrile/waterwith 0.1% trifluoroacetic acid) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-hydroxypropanamido)propanoate) trifluoroacetic acid salt(0.070 mg, 31%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.44 (brs, 1H), 7.89 (dt, J=12.9, 6.0 Hz, 2H) 6.92 (d, J=8.4 Hz, 1H), 6.79 (d,J=8.4 Hz, 1H), 5.51-5.49 (m, 2H), 5.10 (s, 1H), 4.76 (d, J=5.4 Hz, 1H),3.98-3.94 (m, 2H), 3.77 (s, 3H), 3.40-3.20 (m, 7H), 3.04-2.96 (m, 4H),2.65-2.61 (m, 3H), 2.09 (d, J=18.3 Hz, 1H), 1.81 (d, J=12.0 Hz, 1H),1.21 (d, J=4.5 Hz, 3H), 1.19 (d, J=4.2 Hz, 6H); ESI MS m/z 602[C₃₀H₃₉N₃O₁₀+H]⁺; HPLC (Method A) >99% (AUC), t_(R)=7.25 min.

Preparation of(R)-2-((3-((tert-Butoxycarbonyl)amino)propanoyl)oxy)-2-phenylacetic acid

A solution of 3-((tert-butoxycarbonyl)amino)propanoic acid (1.01 g, 5.31mmol) and benzotriazole (703 mg, 5.90 mmol) in tetrahydrofuran (25 mL)was treated with N,N′-dicyclohexylcarbodiimide (1.20 g, 5.82 mmol) andstirred under a nitrogen atmosphere for 4 h. After this time, thereaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The filtrate was cooled in an ice bath and treated with(R)-mandelic acid (511 mg, 3.36 mmol), and 4-dimethylaminopyridine (502mg, 4.11 mmol) and stirred under a nitrogen atmosphere for 65 h. Afterthis time, the reaction mixture was diluted with ethyl acetate (50 mL)and washed with aqueous 10% citric acid (2×25 mL) and water (25 mL). Theorganic layer was extracted with saturated aqueous sodium bicarbonate(3×25 mL). The combined aqueousbicarbonate layers were acidified to pH˜2 with 6 N hydrochloric acid and extracted with ethyl acetate (4×25mL). The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide(R)-2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)-2-phenylacetic acid(1.23 g, quantitative) as a white semi-solid: ¹H NMR (300 MHz, CDCl₃) δ7.50-7.44 (m, 2H), 7.40-7.36 (m, 3H), 6.00 (s, 1H), 3.48-3.38 (m, 2H),2.73-2.59 (m, 2H), 1.43 (s, 9H), CO₂H and NH protons not observed.

Preparation of (R)-2-((2,5-Dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate

A solution of(R)-2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)-2-phenylacetic acid(1.20 g, 3.36 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (434 mg, 3.77 mmol) andN,N′-dicyclohexylcarbodiimide (770 mg, 3.73 mmol) and stirred under anitrogen atmosphere for 2 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide(R)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate (1.54 g, quantitative) as anamber foam: ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.53 (m, 2H), 7.46-7.44 (m,3H), 6.32 (s, 1H), 5.14 (br s, 1H), 3.53-3.43 (m, 2H), 2.82 (br s, 4H),2.72-2.62 (m, 2H), 1.43 (s, 9H).

Preparation of(R)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate

A suspension of oxycodone (804 mg, 2.55 mmol) in tetrahydrofuran (10 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (3.0 mL, 3.0 mmol). Afteraddition was complete, the mixture was stirred in the ice bath for 30min and at ambient temperature for 5 min. The mixture was re-cooled inan ice/brine bath and treated dropwise with a solution of(R)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate (1.54 g, 3.35 mmol) intetrahydrofuran (8 mL). After addition was complete, the mixture wasstirred in the ice/brine bath for 1 h. After this time, the reactionmixture was treated with saturated aqueous ammonium chloride (50 mL) andextracted with ethyl acetate (2×50 mL). The combined organics werewashed with saturated sodium bicarbonate (25 mL) and brine (25 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by column chromatography(silica gel, 0-10% methanol/methylene chloride) followed by reversedphase column chromatography (150 g C18 column, 20-100%acetonitrile/water) and freeze dried to provide(R)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate (111 mg, 7%) as a fluffy whitesolid: ESI MS m/z 621 [C₃₄H₄₀N₂O₉+H]⁺.

Preparation of(R)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-aminopropanoate dihydrochloride

A solution of(R)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate (110 mg, 0.177 mmol) in ethylacetate (3 mL) was treated with a 4.0 M solution of hydrogen chloride in1,4-dioxane (3 mL) and stirred under a nitrogen atmosphere at ambienttemperature for 2 h. After this time, the reaction mixture was dilutedwith diethyl ether and sonicated to produce a solid precipitate. Thesolid was isolated by filtration, washed with diethyl ether, dried undervacuum, and freeze-dried from water to provide(R)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-aminopropanoate dihydrochloride (91 mg, 87%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆, Mixture of diastereomers) δ 9.19 (br s, 1H), 7.91 (brs, 3H), 7.57-7.55 (m, 2H), 7.48-7.46 (m, 3H), 6.87-6.81 (m, 1H),6.76-6.72 (m, 1H), 6.32 (s, 1H), 6.14 (s, 0.42H), 6.13 (s, 0.58H),5.56-5.54 (m, 0.42H), 5.48-5.46 (m, 0.58H), 4.96 (s, 0.42H), 4.92 (s,0.58H), 3.72 (s, 1.74H), 3.67 (br s, 1H), 3.75 (s, 1.26H), 3.42 (d,J=20.4 Hz, 1H), 3.14-3.07 (m, 4H), 2.86-2.83 (m, 5H), 2.64-2.57 (m, 1H),2.49-2.33 (m, 2H, partially obscured by solvent peak), 2.08-2.00 (m,1H), 1.61 (d, J=12.6 Hz, 1H); ESI MS m/z 521 [C₂₉H₃₂N₂O₇+H]⁺; HPLC(Method A) 94.3% (AUC), t_(R)=7.92 min.

Preparation of (S)-1-tert-Butyl4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)amino)succinate

A suspension of oxycodone (0.474 g, 1.50 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated with a 1.0 M solution of potassiumtert-butoxide in tetrahydrofuran (1.65 mL, 1.65 mmol). After additionwas complete, the mixture was stirred under a nitrogen atmosphere in theice bath for 25 min and at ambient temperature for 25 min. The solutionwas re-cooled in an ice/brine bath, and the mixture was treated with asolution of (S)-1-tert-butyl 4-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)amino)succinate (0.637 g, 1.64 mmol) intetrahydrofuran (4 mL) and stirred for 2 h. After this time, thereaction mixture was treated with saturated aqueous ammonium chloride(50 mL) and extracted with ethyl acetate (2×50 mL). The combinedorganics were washed with saturated sodium bicarbonate (50 mL) and brine(50 mL), dried over sodium sulfate, filtered, and concentrated underreduced pressure. The crude residue was purified by columnchromatography (silica gel, 0-4% methanol/methylene chloride) to provide(S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)amino)succinate (0.485 g, 55%) as an off-whitesolid: ESI MS m/z 587 [C₃₁H₄₂N₂O₉+H]⁺.

Preparation of(S)-2-Amino-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid dihydrochloride

A solution of (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)amino)succinate (0.480 g, 0.818 mmol) in1,4-dioxane (15 mL) was treated with 4 N hydrogen chloride in1,4-dioxane (12 mL) at ambient temperature and stirred for 3 h. Afterthis time, the reaction mixture was concentrated under reduced pressureand dried under vacuum toprovide(S)-2-amino-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid dihydrochloride (0.460 g, quantitative) as a white solid: ESI MSm/z 387 [C₂₂H₂₆N₂O₇+H]⁺.

Preparation of(S)-2-((S)-2-((tert-Butoxycarbonyl)oxy)propanamido)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid

A mixture of(S)-2-amino-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid dihydrochloride (0.250 g, 0.496 mmol), (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate (0.214 g, 0.745 mmol), andN,N-diisopropylethylamine (0.43 mL, 2.5 mmol) in methylene chloride (8mL) was stirred at ambient temperature for 2 h. After this time, thereaction mixture was concentrated under reduced pressure. The cruderesidue was purified by reversed phase column chromatography (50 g C18column, 5-100% acetonitrile/water) and freeze dried to provide(S)-2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid (0.050 g, 17%) as a white solid: ESI MS m/z 603 [C₃₀H₃₈N₂O₁₁+H]⁺.

Preparation of(S)-4-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-((S)-2-hydroxypropanamido)-4-oxobutanoicacidtrifluoroacetic acid salt

A solution of(S)-2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid (0.049 g, 0.074 mmol) in methylene chloride (3 mL) was treated withtrifluoroacetic acid (1 mL) and stirred at ambient temperature for 1 h.After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reverse chromatography (50 g C18column, 5-25% acetonitrile/water, with 0.1% TFA) and freeze dried toprovide(S)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-((S)-2-hydroxypropanamido)-4-oxobutanoicacidtrifluoroacetic acid salt (0.032 g, 86%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 12.96 (br s, 1H), 9.17 (br s, 1H), 8.01 (d, J=8.4Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.27 (s, 1H),5.65 (br s, 1H), 5.51 (dd, J=6.0, 2.1 Hz, 1H), 4.97 (s, 1H), 4.66 (q,J=8.1 Hz, 1H), 4.01 (q, J=6.6 Hz, 1H), 3.75 (s, 3H), 3.64 (d, J=6.0 Hz,1H), 3.15-3.01 (m, 3H), 2.96 (d, J=6.3 Hz, 1H), 2.91 (d, J=6.3 Hz, 1H),2.84 (d, J=4.5 Hz, 3H), 2.75-2.55 (m, 1H), 2.32-2.24 (m, 1H), 2.06 (d,J=18.0 Hz, 1H), 1.64 (d, J=10.2 Hz, 1H), 1.21 (d, J=6.6 Hz, 3H); ESI MSm/z 503 [C₂₅H₃₀N₂O₉+H]⁺; HPLC (Method A) 95.0% (AUC), t_(R)=7.03 min.

Preparation of(S)-4-(2-((S)-2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid

A suspension(S)-4-amino-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid dihydrochloride (207 mg, 0.351 mmol) and(S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (150 mg, 0.553 mmol) inmethylene chloride (3 mL) was treated with N,N-diisopropylethylamine(0.24 mL, 1.4 mmol) and stirred under a nitrogen atmosphere for 15 min.After this time, the reaction mixture was diluted with methylenechloride (15 mL) and washed with saturated aqueous ammonium chloride (15mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide(S)-4-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid (234 mg, 99%) as an off-white semi-solid: ESI MS m/z 673[C₃₃H₄₀N₂O₁₃+H]⁺.

Preparation of(S)-4-((S)-3-Carboxy-3-hydroxypropanamido)-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid hydrochloride

A solution of(S)-4-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid (232 mg, 0.345 mmol) in 1,4-dioxane (5 mL) was treated with a 4.0 Msolution of hydrogen chloride in 1,4-dioxane (0.5 mL) followed by water(5 drops) and stirred under a nitrogen atmosphere at ambient temperaturefor 10 min. After this time, the reaction mixture was partiallyconcentrated under reduced pressure, diluted with acetonitrile, andfreeze-dried. The crude product was purified by reversed phase columnchromatography (50 g C18 column, 10-70% acetonitrile/water) and freezedried to provide(S)-4-((S)-3-carboxy-3-hydroxypropanamido)-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid hydrochloride (59 mg, 26%) as a fluffy white solid: ¹H NMR (300MHz, DMSO-d₆) δ 8.41 (d, J=7.2 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.67 (d,J=8.1 Hz, 1H), 5.57 (dd, J=5.7, 2.4 Hz, 1H), 5.14 (q, J=7.2 Hz, 1H),4.87 (s, 1H), 4.41-4.34 (m, 1H), 4.23 (dd, J=8.1, 4.8 Hz, 1H), 3.73 (s,3H), 3.15 (d, J=18.9 Hz, 1H), 2.95 (d, J=5.4 Hz, 1H), 2.73-2.63 (m, 1H),2.49-2.24 (m, 9H, partially obscured by solvent peak), 2.16-1.96 (m,4H), 1.88-1.76 (m, 1H), 1.52 (d, J=7.2 Hz, 3H), two CO₂H, HCl, and twoOH protons not observed, one proton obscured by solvent peaks; ESI MSm/z 633 [C₃₀H₃₆N₂O₁₃+H]⁺; HPLC (Method A) 96.9% (AUC), t_(R)=7.41 min.

Preparation of(S)-2-(((S)-4-(tert-Butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoyl)oxy)propanoicacid

A solution of (S)-1-tert-butyl 4-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)amino)succinate (3.42 g, 8.84 mmol), (S)-lacticacid (963 mg, 10.7 mmol), and 4-dimethylaminopyridine (104 mg, 0.85mmol) in tetrahydrofuran (40 mL) was treated with pyridine (0.85 mL,10.6 mmol) and heated at 50° C. under a nitrogen atmosphere for 16 h.After this time, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (100 mL) and washed with aqueous 10% citric acid (2×50 mL) andwater (50 mL). The organic layer was extracted with saturated aqueoussodium bicarbonate (2×50 mL). The combined aqueous bicarbonate layerswere acidified to pH ˜2 with 6 N hydrochloric acid and extracted withethyl acetate (4×50 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-2-(((S)-4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoyl)oxy)propanoicacid (1.47 mg, 46%) as a white semi-solid: ¹H NMR (300 MHz, CDCl₃) δ5.51-5.48 (m, 1H), 5.17 (q, J=7.2 Hz, 1H), 4.55-4.45 (br m, 1H),2.92-2.89 (m, 2H), 1.54 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 1.44 (s, 9H),CO₂H proton not observed.

Preparation of (S)-1-tert-Butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate

A solution of(S)-2-(((S)-4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoyl)oxy)propanoicacid (1.47 g, 4.05 mmol) in tetrahydrofuran (20 mL) was treated withN-hydroxysuccinimide (513 mg, 4.46 mmol) andN,N′-dicyclohexylcarbodiimide (921 mg, 4.46 mmol) and stirred under anitrogen atmosphere for 4 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide (S)-1-tert-butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate (2.04 g, quantitative) as awhite foam: ¹H NMR (300 MHz, CDCl₃) δ 5.54-5.48 (m, 1H), 5.42 (q, J=7.2Hz, 1H), 4.51-4.45 (m, 1H), 3.08-2.82 (m, 6H), 1.68 (d, J=7.2 Hz, 3H),1.46 (s, 9H), 1.44 (s, 9H).

Preparation of (S)-1-tert-Butyl4-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate

A suspension of oxycodone (574 mg, 1.82 mmol) in tetrahydrofuran (8 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (2.2 mL, 2.2 mmol). Afteraddition was complete, the mixture was stirred in the ice bath for 1.5h. The ice bath was replaced with an ice/brine bath, and the mixture wastreated dropwise with a solution of (S)-1-tert-butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate (992 mg, 2.16 mmol) intetrahydrofuran (8 mL). After addition was complete, the mixture wasstirred in the ice bath for 30 min. After this time, the reactionmixture was treated with saturated aqueous ammonium chloride (50 mL) andextracted with ethyl acetate (2×50 mL). The combined organics werewashed with saturated sodium bicarbonate (50 mL) and brine (50 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by column chromatography(silica gel, 0-10% methanol/methylene chloride) followed by reversedphase column chromatography (150 g C18 column, 20-100%acetonitrile/water) and freeze dried to provide (S)-1-tert-butyl4-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate (244 mg, 20%) as a fluffy whitesolid: ESI MS m/z 659 [C₃₄H₄₆N₂O₁₁+H]⁺.

Preparation of(S)-2-Amino-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid hydrochloride

A solution of (S)-1-tert-butyl4-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate (242 mg, 0.367 mmol) in ethylacetate (3 mL) was treated with a 4.0 M solution of hydrogen chloride in1,4-dioxane (3 mL) and stirred under a nitrogen atmosphere at ambienttemperature for 16 h. After this time, the reaction mixture was dilutedwith diethyl ether and sonicated to produce a solid precipitate. Thesolid was isolated by filtration, washed with diethyl ether, and driedunder vacuum. Half of the material was purified by reversed phase columnchromatography (50 g C18 column, 10-50% acetonitrile/water) and freezedried to provide(S)-2-amino-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid hydrochloride (30 mg, 30%) as a white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 7.77 (br s, 1H), 6.84 (d, J=8.1 Hz, 1H), 6.74 (d, J=8.4 Hz,1H), 5.60-5.58 (m, 1H), 5.13 (q, J=6.9 Hz, 1H), 4.99 (s, 1H), 3.76 (s,3H), 3.64-3.52 (m, 2H), 3.04-2.91 (m, 4H), 2.76-2.63 (m, 5H), 2.49-2.40(m, 1H, partially obscured by solvent peak), 2.28-2.22 (m, 1H), 2.06(apparent d, J=17.4 Hz, 1H), 1.60 (d, J=9.9 Hz, 1H), 1.51 (d, J=6.9 Hz,3H), CO₂H, NH₂, and OH protons not observed; ESI MS m/z 503[C₂₅H₃₀N₂O₉+H]⁺; HPLC (Method A) 96.6% (AUC), t_(R)=6.89 min.

Preparation of(S)-2-((S)-2-((tert-Butoxycarbonyl)oxy)propanamido)-4-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid

A suspension of(S)-2-amino-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid dihydrochloride (105 mg, 0.195 mmol) and(S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)oxy)propanoate (88mg, 0.31 mmol) in methylene chloride (4 mL) was treated withN,N-diisopropylethylamine (0.08 mL, 0.5 mmol) and stirred under anitrogen atmosphere for 15 min. After this time, the reaction mixturewas diluted with methylene chloride (10 mL) and washed with saturatedaqueous ammonium chloride (10 mL). The organic layer was dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (50 gC18 column, 10-100% acetonitrile/water) and freeze dried to provide toprovide(S)-2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (74 mg, 56%) as a fluffy white solid: ESI MS m/z 675[C₃₃H₄₂N₂O₁₃+H]⁺.

Preparation of(S)-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-2-((S)-2-hydroxypropanamido)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(S)-2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (73 mg, 0.11 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (0.5 mL) and stirred under a nitrogen atmosphere atambient temperature for 30 min. After this time, the reaction mixtureconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (15.5 g C18 column, 10-70%acetonitrile/water) and freeze dried to provide to provide(S)-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-2-((S)-2-hydroxypropanamido)-4-oxobutanoicacid trifluoroacetic acid salt (42 mg, 58%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 7.94 (d, J=8.1 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H),6.68 (d, J=8.1 Hz, 1H), 5.64 (d, J=5.1 Hz, 1H), 5.57 (dd, J=5.7, 2.1 Hz,1H), 5.11 (q, J=6.9 Hz, 1H), 4.90 (s, 1H), 4.62-4.55 (m, 1H), 4.00-3.94(m, 1H), 3.74 (s, 3H), 3.20 (d, J=19.8 Hz, 1H, partially obscured bywater peak), 3.08 (br s, 1H), 2.89-2.78 (m, 3H), 2.63-2.57 (m, 1H),2.49-2.31 (m, 2H, partially obscured by solvent peak), 2.17-1.97 (m,2H), 1.48 (d, J=6.9 Hz, 3H), 1.47-1.45 (m, 1H), 1.19 (d, J=6.6 Hz, 3H),CO₂H and CH₃CO₂H protons not observed, four protons obscured by solventpeaks; ESI MS m/z 575 [C₂₈H₃₄N₂O₁₁+H]⁺; HPLC (Method A) 97.1% (AUC),t_(R)=7.78 min.

Preparation of(R)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate

A suspension(S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-aminopropanoate dihydrochloride (47 mg, 0.079 mmol) and(S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (32 mg, 0.12 mmol) inmethylene chloride (2 mL) was treated with N-methylmorpholine (0.04 mL,0.4 mmol) and stirred under a nitrogen atmosphere for 30 min. After thistime, the reaction mixture was diluted with methylene chloride (10 mL)and washed with saturated aqueous ammonium chloride (10 mL). The organiclayer was dried over sodium sulfate, filtered, and concentrated underreduced pressure to provide(R)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate (65mg, quantitative) as an off-white semi-solid: ESI MS m/z 677[C₃₆H₄₀N₂O₁₁+H]⁺.

Preparation of(S)-2-Hydroxy-4-((3-((R)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-3-oxopropyl)amino)-4-oxobutanoicacid hydrochloride

A solution of(R)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate (54mg, 0.079 mmol) in 1,4-dioxane (4 mL) was treated with a 4.0 M solutionof hydrogen chloride in 1,4-dioxane (0.5 mL) followed by water (4 drops)and stirred under a nitrogen atmosphere at ambient temperature for 10min. After this time, the reaction mixture was partially concentratedunder reduced pressure, diluted with acetonitrile, and freeze dried. Thecrude product was purified by reversed phase column chromatography (15.5g C18 column, 10-80% acetonitrile/water) and freeze dried to provide(S)-2-hydroxy-4-((3-((R)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-3-oxopropyl)amino)-4-oxobutanoicacid hydrochloride (26 mg, 49%) as a fluffy white solid: ¹H NMR (300MHz, DMSO-d_(e), Mixture of diastereomers) δ 8.04 (br s, 1H), 7.56-7.54(m, 2H), 7.46-7.44 (m, 3H), 6.75-6.69 (m, 1H), 6.66-6.62 (m, 1H), 6.06(s, 1H), 5.55-5.52 (m, 0.43H), 5.43-5.41 (m, 0.57H), 4.80 (s, 1H),4.24-4.19 (m, 1H), 3.70 (s, 1.71H), 3.61 (s, 1.29H), 3.16-3.09 (m, 1H,partially obscured by water peak), 2.90 (br s, 1H), 2.67-2.58 (m, 2H),2.49-2.22 (m, 8H, partially obscured by solvent peak), 2.12-1.93 (m,3H), 1.39 (d, J=11.4 Hz, 1H), CO₂H and HCl protons not observed, fourprotons obscured by solvent peaks; ESI MS m/z 637 [C₃₃H₃₆N₂O₁₁+H]⁺; HPLC(Method A) 98.2% (AUC), t_(R)=8.52 min.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-Methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate)

A mixture of(4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-aminopropanoate) tris(hydrochloride) (0.520 g, 1.14 mmol),(S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (0.595 g, 1.70 mmol) andN,N-diisopropylethylamine (0.98 mL, 5.7 mmol) in methylene chloride (15mL) was stirred at ambient temperature for 2 h. After this time, thereaction mixture was concentrated under reduced pressure. The cruderesidue was purified by column chromatography (silica gel, 0-10%methanol/methylene chloride) to provide(S)-(4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate)(0.400 g, 38%) as a yellow foam: ESI MS m/z 926 [C₅₀H₅₉N₃O₁₄+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-Methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-hydroxy-2-phenylacetamido)propanoate) trifluoroacetic acidsalt

A solution of(S)-(4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate)(0.400 g, 0.430 mmol) in methylene chloride (6 mL) was treated withtrifluoroacetic acid (3 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The crude residue was purified waspurified by reversed phase column chromatography (50 g C18 column, 5-35%acetonitrile/water, with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-(4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-hydroxy-2-phenylacetamido)propanoate) trifluoroacetic acidsalt (0.0656 g, 21%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.41(br s, 1H), 8.24 (t, J=5.7 Hz, 1H), 8.16 (t, J=5.7 Hz, 1H), 7.40-7.21(m, 10H), 6.92 (d, J=8.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.26 (br s,2H), 5.37-5.35 (m, 1H), 5.07 (s, 1H), 4.91 (d, J=6.0 Hz, 2H), 4.70 (d,J=6.0 Hz, 1H), 3.77 (s, 3H), 3.52 (d, J=20.1 Hz, 1H), 3.38-3.18 (m, 6H),2.99-2.87 (m, 4H), 2.82-2.52 (m, 5H), 2.05 (d, J=18.9 Hz, 1H), 1.78 (d,J=13.5 Hz, 1H); ESI MS m/z 726 [C₄₀H₄₃N₃O₁₀+H]⁺; HPLC (Method A) >99%(AUC), t_(R)=9.14 min.

Preparation of (2S,2′S)-1-d i-tert-Butyl O′4,O4-((4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(2-((tert-butoxycarbonyl)amino)succinate)

A suspension of oxycodone (0.600 g, 1.90 mmol) in tetrahydrofuran (8 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (2.28 mL, 2.28mmol). The mixture was stirred at 0° C. for 15 min and then treateddropwise with a solution of (S)-1-tert-butyl4-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)amino)succinate(0.882 g, 2.28 mmol) in tetrahydrofuran (8 mL). The mixture was stirredat 0° C. for 1 h. After this time, the reaction mixture was treated withsaturated aqueous ammonium chloride (100 mL) and extracted with ethylacetate (3×100 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The cruderesidue was purified by column chromatography (silica gel, 0-3%methanol/methylene chloride) to provide (2S,2′S)-1-di-tert-butyl O′4,O4-((4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(2-((tert-butoxycarbonyl)amino)succinate)(0.490 g, 44%) as a whitefoam: ESI MS m/z 858 [C₄₄H₆₃N₃O₁₄+H]⁺.

Preparation of(2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-Methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-amino-4-oxobutanoicacid) tris(trifluoroacetic acid salt)

A solution of (2S,2′S)-1-di-tert-butyl 0′4,04-((4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(2-((tert-butoxycarbonyl)amino)succinate) (0.100 g, 0.116 mmol) inmethylene chloride (8 mL) was treated with trifluoroacetic acid (2.5 mL)and stirred at ambient temperature for 1 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas purified by reversed phase column chromatography (50 g C18 column,5-30% acetonitrile/water) and freeze dried to provide(2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-amino-4-oxobutanoicacid)tris(trifluoroacetic acid salt)(0.0515 g, 81%) as a fluffy whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.85-7.92 (br s, 6H), 6.92 (d, J=8.1Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 5.54-5.52 (m, 1H), 5.07 (s, 1H), 4.67(d, J=6.0 Hz, 1H), 4.27 (t, J=5.7 Hz, 1H), 3.93 (t, J=8.7 Hz, 1H), 3.77(s, 3H), 3.50 (d, J=20.1 Hz, 1H), 3.21-2.97 (m, 5H), 2.81 (s, 3H),2.77-2.65 (m, 4H), 2.13 (d, J=18.3 Hz, 1H), 1.77 (d, J=11.4 Hz, 1H), twoCO₂H protons not observed; ESI MS m/z 546 [C₂₆H₃₁N₃O₁₀+H]⁺; HPLC (MethodA) 95.6% (AUC), t_(R)=6.11 min.

Preparation of tert-Butyl (2,5-dioxopyrrolidin-1-yl) succinate

A mixture of 4-(tert-butoxy)-4-oxobutanoic acid (9.75 g, 56.0 mmol) andN-hydroxysuccinimide (7.00 g, 60.8 mmol) in tetrahydrofuran (280 mL) at0° C. was treated with N,N′-dicyclohexylcarbodiimide (12.5 g, 60.8mmol). The ice bath was removed, and the reaction mixture was stirred atambient temperature for 4 h. After this time, diethyl ether (100 mL) wasadded, and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide tert-butyl (2,5-dioxopyrrolidin-1-yl)succinate (15.0 g) that was used without purification: ¹H NMR (300 MHz,CDCl₃) δ 2.91 (t, J=7.2 Hz, 2H), 2.83 (s, 4H), 2.66 (t, J=7.2 Hz, 2H),1.46 (s, 9H).

Preparation of (S)-2-((4-(tert-Butoxy)-4-oxobutanoyl)oxy)propanoic acid

A mixture of tert-butyl (2,5-dioxopyrrolidin-1-yl) succinate (7.60 g,28.0 mmol), (S)-2-hydroxypropanoic acid (3.00 g, 33.3 mmol), pyridine(2.7 mL, 33.5 mmol), and 4-dimethylaminopyridine (200 mg, 1.6 mmol) intetrahydrofuran (120 mL) was stirred at reflux for 24 h. After thistime, the mixture was cooled to room temperature, partially concentratedunder reduced pressure, diluted with ethyl acetate, and washed with 10%citric acid. The organic layer was extracted with saturated sodiumbicarbonate. The aqueous extract was carefully treated with 2Nhydrochloric acid until acidic by pH paper analysis, and then extractedwith ethyl acetate. The organic extracts were dried over sodium sulfate,filtered, and concentrated to give(S)-2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic acid (4.84 g, 70%):ESI MS m/z 245 [C₁₁H₁₈O₆−H]⁻

Preparation of (S)-tert-Butyl(1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl) succinate

A mixture of (S)-2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic acid(4.80 g, 19.5 mmol) and N-hydroxysuccinimide (2.50 g, 21.7 mmol) intetrahydrofuran (100 mL) at 0° C. was treated withN,N′-dicyclohexylcarbodiimide (4.45 g, 21.6 mmol). The ice bath wasremoved, and the reaction mixture was stirred at ambient temperature for4 h. After this time, diethyl ether (100 mL) was added, and the mixturewas filtered. The filtrate was concentrated under reduced pressure toprovide (S)-tert-butyl(1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl) succinate (6.85 g)that was used without purification: ¹H NMR (300 MHz, CDCl₃) δ 5.44 (q,J=7.1 Hz, 1H), 2.84 (s, 4H), 2.72-2.52 (m, 4H), 1.68 (d, J=7.1 Hz, 3H),1.44 (s, 9H).

Preparation of tert-Butyl((S)-1-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)succinate

A suspension of oxycodone (0.600 g, 1.90 mmol) in tetrahydrofuran (6 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (2.47 mL, 2.47mmol). The mixture was stirred at 0° C. for 15 min and then treateddropwise with a solution of (S)-tert-butyl(1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl) succinate (0.849 g,2.47 mmol) in tetrahydrofuran (6 mL). The mixture was stirred at 0° C.for 1 h. After this time, the reaction mixture was treated withsaturated aqueous ammonium chloride (100 mL) and extracted with ethylacetate (3×100 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The cruderesidue was purified by reversed phase column chromatography (50 g C18column, 5-100% acetonitrile/water) and freeze dried to providetert-butyl((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)succinate (0.460 g, 44%) as a colorless oil: ESI MS m/z 544[C₂₉H₃₇NO₉+H]⁺.

Preparation of4-(((R)-1-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacidtrifluoroacetic acid salt

A solution of tert-butyl((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)succinate (0.210 g, 0.386 mmol) in methylene chloride (6 mL) was treatedwith trifluoroacetic acid (3 mL) and stirred under a nitrogen atmosphereat ambient temperature for 1 h. After this time, the reaction mixturewas concentrated under reduced pressure. The crude residue was purifiedby reversed phase column chromatography (50 g C18 column, 5-50%acetonitrile/water) and freeze dried to provide4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (0.098 g, 52%) as a fluffy white solid:¹H NMR (300 MHz, DMSO-d₆) δ 12.25 (br s, 1H), 9.19 (s, 1H), 6.86 (d,J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.31 (br s, 1H), 5.59-5.57 (m,1H), 5.11 (q, J=6.9 Hz, 1H), 4.99 (s, 1H), 3.75 (s, 3H), 3.65 (d, J=6.0Hz, 2H), 3.43 (d, J=19.8 Hz, 1H), 3.14-3.31 (m, 2H), 2.84 (d, J=4.5 Hz,3H), 2.62-2.60 (m, 3H), 2.48-2.40 (m, 2H), 2.29 (dd, J=17.7, 11.7 Hz,1H), 2.06 (d, J=18.0 Hz, 1H), 1.65 (d, J=11.1 Hz, 1H), 1.49 (d, J=3.9Hz, 3H); ESI MS m/z 488 [C₂₅H₂₉NO₉+H]⁺; HPLC (Method A) 97.3% (AUC),t_(R)=8.19 min.

Preparation of(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-Methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobonzofuro[3,2-e]isoquinolino-4a,7-diyl)bis(oxy))bis(2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-4-oxobutanoicacid)

A mixture of(2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-Methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-amino-4-oxobutanoicacid) tris(trifluoroacetic acid salt) (0.200 g, 0.225 mmol),(S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)oxy)propanoate(0.194 g, 0.676 mmol), and N,N-diisopropylethylamine (0.23 mL, 1.4 mmol)in methylene chloride (5 mL) was stirred at ambient temperature for 2 h.After this time, the reaction was concentrated under reduced pressure togive(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-4-oxobutanoicacid) (0.600 g, crude) as a white foam: ESI MS m/z 890 [C₄₂H₅₅N₃O₁₈+H]⁺.

Preparation of(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-Methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-((S)-2-hydroxypropanamido)-4-oxobutanoicacid) trifluoroacetic acid salt

A solution of(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-4-oxobutanoicacid)(0.600 g, crude) in methylene chloride (6 mL) was treated withtrifluoroacetic acid (3 mL) and stirred at ambient temperature for 1 h.After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase chromatography (50g C18 column, 5-20% acetonitrile/water, with 0.1% trifluoroacetic acid)and freeze dried to provide(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-((S)-2-hydroxypropanamido)-4-oxobutanoicacid)trifluoroacetic acid salt (0.0135 g, 7% over two steps) as a whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.96 (br s, 2H), 9.35 (br s, 1H),8.03 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H),6.77 (d, J=8.4 Hz, 1H), 5.68 (br s, 2H), 5.44-5.42 (m, 1H), 5.03 (s,1H), 4.69-4.62 (m, 3H), 4.03-3.97 (m, 2H), 3.76 (s, 3H), 3.28-3.13 (m,1H), 3.16-3.07 (m, 2H), 3.04-2.82 (m, 8H), 2.73-2.63 (m, 2H), 2.11 (d,J=18.3 Hz, 1H), 1.76 (d, J=12.9 Hz, 1H), 1.20 (d, J=9.0 Hz, 6H); ESI MSm/z 690 [C₃₂H₃₉N₃O₁₄+H]⁺; HPLC (Method A) 83.1% (AUC), t_(R)=7.13 min.

Preparation of (S)-4-tert-Butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)oxy)succinate

A mixture of(S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoic acid(2.70 g, 9.31 mmol) and N-hydroxysuccinimide (1.25 g, 10.9 mmol) intetrahydrofuran (50 mL) at 0° C. was treated withN,N′-dicyclohexylcarbodiimide (2.20 g, 10.7 mmol). The ice bath wasremoved, and the reaction mixture was stirred at ambient temperature for4 h. After this time, diethyl ether (100 mL) was added, and the mixturewas filtered. The filtrate was concentrated under reduced pressure toprovide (S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)oxy)succinate (3.78 g) that was used withoutpurification: ¹H NMR (300 MHz, CDCl₃) δ 5.61 (dd, J=8.0, 4.8 Hz, 1H),2.98-2.93 (m, 2H), 2.84 (s, 4H), 1.51 (s, 9H), 1.47 (s, 9H).

Preparation of(S)-2-(((S)-4-(tert-Butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoyl)oxy)propanoicacid

A mixture of (S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)oxy)succinate (3.38 g, 8.73 mmol),(S)-2-hydroxypropanoic acid (1.20 g, 13.3 mmol), pyridine (1.1 mL, 14mmol), and 4-dimethylaminopyridine (100 mg, 0.8 mmol) in tetrahydrofuran(40 mL) was stirred at reflux for 18 h. After this time, the mixture wascooled to room temperature, partially concentrated under reducedpressure, diluted with ethyl acetate, and washed with 10% citric acid.The organic layer was extracted with saturated sodium bicarbonate. Theaqueous extract was carefully treated with 2N hydrochloric acid untilacidic by pH paper analysis, and then extracted with ethyl acetate. Theorganic extracts were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to give(S)-2-(((S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoyl)oxy)propanoicacid (1.58 g, 50%): ¹H NMR (300 MHz, CDCl₃) δ 5.37-5.22 (m, 2H),2.96-2.82 (m, 2H), 1.57 (d, J=7.1 Hz, 3H), 1.49 (s, 9H), 1.46 (s, 9H),CO₂H proton not observed.

Preparation of (S)-4-tert-Butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate

A mixture of(S)-2-(((S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoyl)oxy)propanoicacid (1.58 g, 4.36 mmol) and N-hydroxysuccinimide (550 mg, 4.78 mmol) intetrahydrofuran (30 mL) at 0° C. was treated withN,N′-dicyclohexylcarbodiimide (990 mg, 4.80 mmol). The ice bath wasremoved, and the reaction mixture was stirred at ambient temperature for4 h. After this time, diethyl ether (30 mL) was added, and the mixturewas filtered. The filtrate was concentrated under reduced pressure toprovide (S)-4-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate (2.2 g) that was used withoutpurification: ¹H NMR (300 MHz, CDCl₃) δ 5.56 (q, J=7.1 Hz, 1H), 3.37(dd, J=8.8, 3.9 Hz, 1H), 2.98-2.93 (m, 2H), 2.84 (s, 4H), 1.72 (d, J=7.1Hz, 3H), 1.50 (s, 9H), 1.46 (s, 9H).

Preparation of (S)-4-tert-Butyl1-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate

A suspension of oxycodone (0.550 g, 1.75 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated with a 1.0 M solution of potassiumtert-butoxide in tetrahydrofuran (1.95 mL, 1.95 mmol). After additionwas complete, the mixture was stirred under a nitrogen atmosphere in theice bath for 25 min and at ambient temperature for 25 min. The solutionwas re-cooled in a dry ice/acetone bath, and the mixture was treatedwith a solution of (S)-4-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate (0.900 g, 1.96 mmol) intetrahydrofuran (5 mL). The temperature was allowed to slowly increaseto 0° C. over 2 h. After this time, the reaction mixture was treatedwith saturated aqueous ammonium chloride (50 mL) and extracted withethyl acetate (2×50 mL). The combined organics were washed withsaturated sodium bicarbonate (50 mL) and brine (50 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (150g C18 column, 5-100% acetonitrile/water) and freeze dried to provide(S)-4-tert-butyl1-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate (273 mg, 24%) as a white solid:ESI MS m/z 660 [C₃₄H₄₅NO₁₂+H]⁺.

Preparation of(S)-3-Hydroxy-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of (S)-4-tert-butyl1-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate (0.260 g, 0.390 mmol) in methylenechloride (6 mL) was treated with trifluoroacetic acid (3 mL) and stirredat ambient temperature for 1 h. After this time, the reaction mixturewas concentrated under reduced pressure. The crude residue was purifiedby reversed phase column chromatography (50 g C18 column, 5-50%acetonitrile/water) and freeze dried to provide(S)-3-hydroxy-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacidtrifluoroacetic acid salt (0.122 g, 62%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 12.36 (br s, 1H), 9.19 (br s, 1H), 6.86 (d, J=8.4Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.31 (s, 1H), 5.83 (br s, 1H),5.60-5.58 (m, 1H), 5.18 (q, J=16.2 Hz, 1H), 5.00 (s, 1H), 4.73 (dd,J=8.7, 3.9 Hz, 1H), 3.75 (s, 3H), 3.65 (d, J=6.3 Hz, 1H), 3.43 (d,J=20.1 Hz, 1H), 3.14-3.07 (m, 2H), 2.84 (d, J=4.8 Hz, 3H), 2.78-2.58 (m,2H), 2.33-2.26 (m, 1H), 2.07 (d, J=17.7 Hz, 1H), 1.65 (d, J=11.4 Hz,1H), 1.51 (d, J=7.2 Hz, 3H), one proton obscured by solvent peaks; ESIMS m/z 504 [C₂₅H₂₉N₁₀+H]⁺; HPLC (Method A) 98.6% (AUC), t_(R)=7.62 min.

Preparation of (S)-2-((4-(tert-Butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid

A mixture of tert-butyl (2,5-dioxopyrrolidin-1-yl) succinate (7.60 g,28.0 mmol), (S)-2-hydroxy-2-phenylacetic acid (4.26 g, 28.0 mmol),pyridine (2.7 mL, 33.5 mmol), and 4-dimethylaminopyridine (200 mg, 1.6mmol) in tetrahydrofuran (120 mL) was stirred at reflux for 48 h. Afterthis time, the mixture was cooled to room temperature, partiallyconcentrated under reduced pressure, diluted with ethyl acetate, andwashed with 10% citric acid. The organic layer was extracted withsaturated sodium bicarbonate. The aqueous extract was carefully treatedwith 2N hydrochloric acid until acidic by pH paper analysis, and thenextracted with ethyl acetate. The organic extracts were dried oversodium sulfate, filtered, and concentrated to give(S)-2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylacetic acid (6.00 g,70%): ¹H NMR (300 MHz, CDCl₃) δ 7.51-7.45 (m, 2H), 7.42-7.35 (m, 3H),5.97 (s, 1H), 2.76-2.69 (m, 2H), 2.63-2.55 (m, 2H), 1.41 (s, 9H), CO₂Hproton not observed.

Preparation of (S)-tert-Butyl(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl) succinate

A mixture of (S)-2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid (6.00 g, 19.5 mmol) and N-hydroxysuccinimide (2.50 g, 21.7 mmol) intetrahydrofuran (100 mL) at 0° C. was treated withN,N-dicyclohexylcarbodiimide (4.45 g, 21.6 mmol). The ice bath wasremoved, and the reaction mixture was stirred at ambient temperature for4 h. After this time, diethyl ether (100 mL) was added, and the mixturewas filtered. The filtrate was concentrated under reduced pressure toprovide (S)-tert-butyl(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl) succinate (8.33g) that was used without purification: ¹H NMR (300 MHz, CDCl₃) δ7.57-7.51 (m, 2H), 7.46-7.40 (m, 3H), 6.35 (s, 1H), 2.80 (s, 4H),2.77-2.71 (m, 2H), 2.63-2.56 (m, 2H), 1.41 (s, 9H).

Preparation of tert-butyl((S)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)succinate

A suspension of oxycodone (0.600 g, 1.90 mmol) in tetrahydrofuran (6.0mL) was cooled in an ice bath and treated dropwise with a 1.0 M solutionof lithium bis(trimethylsilyl)amide in tetrahydrofuran (3.0 mL, 3.0mmol). The mixture was stirred at 0° C. for 15 min and then treateddropwise with a solution of (S)-tert-butyl(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl) succinate (1.20g, 3.04 mmol) in tetrahydrofuran (6 mL). The mixture was stirred at 0°C. for 1 h. After this time, the reaction mixture was treated withsaturated aqueous ammonium chloride (100 mL) and extracted with ethylacetate (3×100 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The cruderesidue was purified by reversed phase chromatography (150 g C18 column,5-100% acetonitrile/water) and freeze dried to provide tert-butyl((S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)succinate (0.540 g, 47%) as a colorless oil: ESI MS m/z 606[C₃₄H₃₉NO₉+H]⁺.

Preparation of4-((R)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of tert-butyl((R)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)succinate (0.250 g, 0.413 mmol) in methylene chloride (6 mL) was treatedwith trifluoroacetic acid (3 mL) and stirred under a nitrogen atmosphereat ambient temperature for 1 h. After this time, the reaction mixturewas concentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 5-50%acetonitrile/water) and freeze dried to provide4-((S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacidtrifluoroacetic acid salt (0.100 mg, 44%) as a fluffy white solid:¹H NMR (300 MHz, DMSO-d₆) δ 12.28 (br s, 1H), 9.16 (br s, 1H), 7.56-7.54(m, 2H), 7.50-7.45 (m, 3H), 6.81 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.4 Hz,1H), 6.31 (s, 1H), 6.10 (s, 1H), 5.55-5.53 (m, 1H), 4.95 (s, 1H), 3.64(s, 3H), 3.41 (d, J=19.8 Hz, 1H), 3.14-3.05 (m, 2H), 2.83 (d, J=4.5 Hz,3H), 2.69-2.66 (m, 3H), 2.56-2.49 (m, 2H), 2.45-2.40 (m, 1H), 2.30-2.22(m, 1H), 2.05 (d, J=18.3 Hz, 1H), 1.62 (d, J=11.4 Hz, 1H); ESI MS m/z550 [C₃₀H₃₁NO₉+H]⁺; HPLC (Method A) 99.0% (AUC), t_(R)=9.30 min.

Preparation of(S)-2-((S)-2-((tert-Butoxycarbonyl)oxy)-2-phenylacetoxy)propanoic acid

A solution of (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (2.00 g, 5.73 mmol), lacticacid (627 mg, 6.96 mmol), and 4-dimethylaminopyridine (68 mg, 0.56 mmol)in tetrahydrofuran (25 mL) was treated with pyridine (0.56 g, 7.0 mmol)and heated at 50° C. under a nitrogen atmosphere for 16 h. After thistime, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (50 mL) and washed with aqueous 10% citric acid (2×25 mL) andwater (25 mL). The organic layer was extracted with saturated aqueoussodium bicarbonate (2×25 mL). The combined aqueous bicarbonate layerswere acidified to pH ˜2 with 6 N hydrochloric acid and extracted withethyl acetate (4×25 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure toprovide(S)-2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoicacid (1.42 g, 76%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ7.52-7.48 (m, 2H), 7.40-7.37 (m, 3H), 5.85 (s, 1H), 5.23 (q, J=6.9 Hz,1H), 1.56-1.44 (m, 12H), CO₂H proton not observed; ESI MS m/z 647[(2×C₁₆H₂₀O₇)−H]⁻.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoate

A solution of(S)-2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoic acid(1.42 g, 4.36 mmol) in tetrahydrofuran (20 mL) was treated withN-hydroxysuccinimide (558 mg, 4.85 mmol) andN,N′-dicyclohexylcarbodiimide (997 mg, 4.83 mmol) and stirred under anitrogen atmosphere for 2.5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide(S)-2,5-dioxopyrrolidin-1-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoate (2.02 g,quantitative) as a white crushable foam: ¹H NMR (300 MHz, CDCl₃) δ7.51-7.45 (m, 2H), 7.40-7.34 (m, 3H), 5.85 (s, 1H), 5.53 (q, J=6.9 Hz,1H), 2.82 (br s, 4H), 1.69 (d, J=6.9 Hz, 3H), 1.51 (s, 9H).

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoate

A suspension of oxycodone (502 mg, 1.59 mmol) in tetrahydrofuran (6 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (1.9 mL, 1.9 mmol). Afteraddition was complete, the mixture was stirred in the ice bath for 10min and at ambient temperature for 5 min. The mixture was re-cooled inthe ice bath and treated dropwise with a solution of(S)-2,5-dioxopyrrolidin-1-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoate (806 mg,1.91 mmol) in tetrahydrofuran (6 mL). After addition was complete, themixture was stirred at ambient temperature for 10 min. After this time,the reaction mixture was re-cooled in the ice bath and treated withsaturated aqueous ammonium chloride (50 mL) and extracted with ethylacetate (2×50 mL). The combined organics were washed with saturatedsodium bicarbonate (25 mL) and brine (25 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (silica gel, 0-10% methanol/methylenechloride) followed by reversed phase column chromatography (50 g C18column, 20-100% acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoate (53 mg,5%) as a fluffy white solid: ESI MS m/z 622 [C₃₄H₃₉NO₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-hydroxy-2-phenylacetoxy)propanoate trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoate (53 mg,0.085 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (0.5 mL) and stirred under a nitrogen atmosphere atambient temperature for 20 min. After this time, the reaction mixtureconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 10-70%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-hydroxy-2-phenylacetoxy)propanoate trifluoroacetic acid salt(24 mg, 45%) as a fluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.17(br s, 1H), 7.46-7.42 (m, 2H), 7.37-7.27 (m, 3H), 6.85 (d, J=8.4 Hz,1H), 6.74 (d, J=8.1 Hz, 1H), 6.26 (s, 1H), 6.15 (d, J=5.4 Hz, 1H),5.50-5.48 (m, 1H), 5.23-5.16 (m, 1H), 4.84 (s, 1H), 3.72 (s, 3H), 3.64(br s, 1H), 3.42 (d, J=20.1 Hz, 1H), 3.15-3.06 (m, 2H), 2.84 (s, 3H),2.64-2.57 (m, 1H), 2.49-2.40 (m, 1H, partially obscured by solventpeak), 2.34-2.23 (m, 1H), 2.04 (apparent d, J=18.3 Hz, 1H), 1.62 (d,J=8.7 Hz, 1H), 1.48 (d, J=6.9 Hz, 3H); ESI MS m/z 522 [C₂₉H₃₁NO₈+H]⁺.

Preparation of (S,Z)-2-(Oleoyloxy)-2-phenylacetic acid

A solution of oleoyl chloride (2.13 g, 7.08 mmol) in methylene chloride(35 mL) was cooled in an ice bath and treated with (S)-mandelic acid(1.08 g, 7.08 mmol) and N,N-diisopropylethylamine (2.75 g, 21.2 mmol)and stirred under a nitrogen for 5 h. After this time, 10% aqueouscitric acid (100 mL) was added, and the resulting mixture was extractedwith ethyl acetate (2×100 mL). The combined organics were washed withbrine (100 mL), dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography (80 g silica gel column, 0-50% ethyl acetate/heptane) toprovide of (S,Z)-2-(oleoyloxy)-2-phenylacetic acid (1.26 g, 42%) as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.50-7.46 (m, 2H), 7.41-7.37(m, 3H), 5.95 (s, 1H), 5.36-5.32 (m, 2H), 2.47 (m, 2H), 1.99 (m, 4H),1.66 (m, 2H), 1.27 (m, 20H), 0.87 (t, J=6.6 Hz, 3H), CO₂H proton notobserved.

Preparation of (S)-2-((2,5-Dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyloleate

A solution of (S,Z)-2-(oleoyloxy)-2-phenylacetic acid (1.26 g, 3.02mmol) in tetrahydrofuran (30 mL) was treated with N-hydroxysuccinimide(383 mg, 3.33 mmol) and N,N′-dicyclohexylcarbodiimide (686 mg, 3.33mmol) and stirred under a nitrogen atmosphere for 5 h. After this time,the reaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether (100 mL), and thecombined filtrate and washings were concentrated under reduced pressure.The residue was triturated with diethyl ether to provide(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl oleate (1.68g) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.61-7.53 (m, 2H),7.46-7.42 (m, 3H), 6.34 (s, 1H), 5.36-5.32 (m, 2H), 2.87 (s, 4H), 2.45(m, 2H), 1.99 (m, 4H), 1.66 (m, 2H), 1.27 (m, 20H), 0.88 (t, J=6.6 Hz,3H).

Preparation of(S)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyloleate trifluoroacetic acid salt

A suspension of oxycodone (461 mg, 1.46 mmol) in tetrahydrofuran (7 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (1.8 mL, 1.8 mmol). Afteraddition was complete, the mixture was stirred in the ice bath for 45min. The ice bath was replaced with an ice/brine bath, and the mixturewas treated dropwise with a suspension of(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl oleate (900mg, 1.75 mmol) in tetrahydrofuran (7 mL). The mixture was stirred in theice/brine bath under a nitrogen atmosphere for 45 min. After this time,the reaction mixture was treated with saturated aqueous ammoniumchloride (50 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organics were washed with saturated sodium bicarbonate (50 mL),water (50 mL), and brine (50 mL); dried over sodium sulfate; filtered;and concentrated under reduced pressure. The crude residue was purifiedby column chromatography (silica gel, 0-10% methanol/methylene chloride)followed by reversed phase column chromatography (150 g C18 column,50-100% acetonitrile/water with 0.1% trifluoroacetic acid) and freezedried to provide(S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyloleatetrifluoroacetic acid salt (265 mg, 22%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆, Mixture of diastereomers) δ 9.17 (br s, 1H),7.56-7.53 (m, 2H), 7.46-7.44 (m, 3H), 6.85-6.79 (m, 1H), 6.75-6.71 (m,1H), 6.29 (s, 1H), 6.09 (s, 0.49H), 6.07 (s, 0.51H), 5.53 (dd, J=6.0,2.1 Hz, 0.49H), 5.45 (dd, J=6.0, 2.1 Hz, 0.51H), 5.33-5.30 (m, 2H), 4.94(s, 0.49H), 4.90 (s, 0.51H), 3.71 (s, 1.47H), 3.64 (br s, 2.53H),3.45-3.38 (m, 1H), 3.13-3.05 (m, 2H), 2.82 (s, 3H), 2.64-2.55 (m, 1H),2.49-2.40 (m, 3H, partially obscured by solvent peak), 2.28-2.22 (m,1H), 2.07-1.96 (m, 5H), 1.64-1.54 (m, 3H), 1.32-1.24 (m, 20H), 0.84 (t,J=6.6 Hz, 3H); ESI MS m/z 714 [C₄₄H₅₉NO₇+H]⁺; HPLC (Method A) >99%(AUC), t_(R)=16.02 min.

Preparation of (S)-2-Phenyl-2-(stearoyloxy)acetic acid

A solution of stearoyl chloride (364 mg, 1.20 mmol) in methylenechloride (5 mL) was cooled in an ice bath and treated with (S)-mandelicacid (182 mg, 1.20 mmol) and N,N-diisopropylethylamine (465 mg, 3.60mmol) and stirred under a nitrogen atmosphere for 16 h. After this time,10% aqueous citric acid (10 mL) was added, and the resulting mixture wasextracted with ethyl acetate (2×20 mL). The combined organics werewashed with brine (50 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography (40 g silica gel column, 0-100% ethyl acetate/heptane) toprovide of (S)-2-phenyl-2-(stearoyloxy)acetic acid (140 mg, 28%) as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.51-7.47 (m, 2H), 7.42-7.39(m, 3H), 5.97 (s, 1H), 2.45 (m, 2H), 1.68 (m, 3H), 1.27 (m, 28H), 0.88(t, J=6.6 Hz, 3H).

Preparation of (S)-2-((2,5-Dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethylstearate

A solution of (S)-2-phenyl-2-(stearoyloxy)acetic acid (140 mg, 0.334mmol) in tetrahydrofuran (3 mL) was treated with N-hydroxysuccinimide(42 mg, 0.368 mmol) and N,N′-dicyclohexylcarbodiimide (76 mg, 0.368mmol) and stirred under a nitrogen atmosphere for 5 h. After this time,the reaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether (100 mL), and thecombined filtrate and washings were concentrated under reduced pressure.The residue was triturated with diethyl ether to provide(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl stearate (191mg) as a white powder: ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.53 (m, 2H),7.46-7.43 (m, 3H), 6.34 (s, 1H), 2.81 (s, 4H), 2.46 (m, 2H), 1.68 (m,2H), 1.24 (m, 28H), 0.88 (t, J=6.6 Hz, 3H).

Preparation of(S)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethylstearate trifluoroacetic acid salt

A suspension of oxycodone (515 mg, 1.63 mmol) in tetrahydrofuran (9 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (2.0 mL, 2.0 mmol). Afteraddition was complete, the mixture was stirred in the ice bath for 45min. The ice bath was replaced with an ice/brine bath, and the mixturewas treated dropwise with a suspension of(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl stearate (1.01g, 1.96 mmol) in tetrahydrofuran (7 mL). The mixture was stirred in theice/brine bath under a nitrogen atmosphere for 45 min. After this time,the reaction mixture was treated with saturated aqueous ammoniumchloride (50 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organics were washed with saturated sodium bicarbonate (50 mL),water (50 mL), and brine (50 mL); dried over sodium sulfate; filtered;and concentrated under reduced pressure. The crude residue was purifiedby column chromatography (silica gel, 0-10% methanol/methylene chloride)followed by reversed phase column chromatography (150 g C18 column,50-100% acetonitrile/water with 0.1% trifluoroacetic acid) and freezedried to(S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethylstearate trifluoroacetic acid salt (430 mg, 32%) as a white solid: ¹HNMR (300 MHz, DMSO-d₆, Mixture of diastereomers) δ 9.17 (br s, 1H),7.56-7.53 (m, 2H), 7.46-7.44 (m, 3H), 6.86-6.80 (m, 1H), 6.75-6.71 (m,1H), 6.30 (br s, 1H), 6.09 (s, 0.51H), 6.07 (s, 0.49H), 5.53 (dd, J=6.0,2.1 Hz, 0.51H), 5.45 (dd, J=6.0, 2.1 Hz, 0.49H), 4.94 (s, 0.51H), 4.90(s, 0.49H), 3.71 (s, 1.53H), 3.64 (br s, 2.47H), 3.45-3.35 (m, 1H),3.13-3.05 (m, 2H), 2.83 (apparent d, J=4.5 Hz, 3H), 2.67-2.55 (m, 1H),2.49-2.40 (m, 3H, partially obscured by solvent peak), 2.30-2.22 (m,1H), 2.08-2.01 (m, 1H), 1.64-1.51 (m, 3H), 1.32-1.23 (m, 28H), 0.85 (t,J=6.6 Hz, 3H); ESI MS m/z 716 [C₄₄H₆₁NO₇+H]⁺; HPLC (Method A) 99.0%(AUC), t_(R)=16.53 min.

Preparation of (S)-2-(Stearoyloxy)propanoic acid

A solution of stearic acid (5.02 g, 17.6 mmol) and benzotriazole (2.31g, 19.4 mmol) in tetrahydrofuran (80 mL) was treated withN,N′-dicyclohexylcarbodiimide (4.00 g, 19.4 mmol) and stirred under anitrogen atmosphere for 5.5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct, and the solidswere washed with diethyl ether. The combined filtrate and washings wereconcentrated. The residue was dissolved in tetrahydrofuran (90 mL) andcooled in an ice bath. The mixture was treated with lactic acid (1.61 g,17.9 mmol) and 4-dimethylaminopyridine (2.18 g, 17.8 mmol), and the icebath was removed. The mixture was stirred at ambient temperature under anitrogen atmosphere for 40 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate (250 mL) and washed with aqueous 10% citric acid (2×100 mL) andwater (100 mL). The organic layer was extracted with saturated aqueoussodium bicarbonate (2×100 mL). The combined aqueousbicarbonate layerswere acidified to pH ˜1 with 6 N hydrochloric acid and extracted withethyl acetate (2×100 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas dissolved/suspended in heptanes (100 mL), filtered to removeundissolved solids, washed with aqueous 10% citric acid (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide (S)-2-(stearoyloxy)propanoic acid (4.86 g, 77%) as acolorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.12 (q, J=7.2 Hz, 1H),2.41-2.32 (m, 2H), 1.67-1.52 (m, 5H), 1.31-1.27 (m, 28H), 0.88 (t, J=6.3Hz, 3H), CO₂H proton not observed.

Preparation of (S)-1-((2,5-Dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-ylstearate

A solution of (S)-2-(stearoyloxy)propanoic acid (4.85 g, 13.6 mmol) intetrahydrofuran (80 mL) was treated with N-hydroxysuccinimide (1.57 mg,13.6 mmol) and N,N′-dicyclohexylcarbodiimide (2.80 g, 13.6 mmol) andstirred under a nitrogen atmosphere for 1.5 h. After this time, thereaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether, and the combinedfiltrate and washings were concentrated under reduced pressure toprovide (S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl stearate(6.69 g, quantitative) as a white crushable foam: ¹H NMR (300 MHz,CDCl₃) δ 5.42 (q, J=7.2 Hz, 1H), 2.84 (br s, 4H), 2.42-2.37 (m, 2H),1.73-1.53 (m, 5H), 1.31-1.27 (m, 28H), 0.88 (t, J=6.3 Hz, 3H).

Preparation of(S)-1-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-ylstearate trifluoroacetic acid salt

A suspension of oxycodone (582 mg, 1.85 mmol) in tetrahydrofuran (9 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (2.3 mL, 2.3 mmol). Afteraddition was complete, the mixture was stirred in the ice bath for 45min. The ice bath was replaced with an ice/brine bath, and the mixturewas treated dropwise with a solution of(S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl stearate (1.01 g,2.23 mmol) in tetrahydrofuran (9 mL). The mixture was stirred in theice/brine bath under a nitrogen atmosphere for 20 min. After this time,the reaction mixture was treated with saturated aqueous ammoniumchloride (50 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organics were washed with saturated sodium bicarbonate (50 mL)and brine (50 mL), dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude residue was purified by columnchromatography (silica gel, 0-10% methanol/methylene chloride) followedby reversed phase column chromatography (150 g C18 column, 50-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-ylstearatetrifluoroacetic acid salt (94 mg, 8%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 9.17 (br s, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.75 (d,J=8.4 Hz, 1H), 6.29 (br s, 1H), 5.58 (dd, J=5.7, 1.8 Hz, 1H), 5.10 (q,J=6.9 Hz, 1H), 4.99 (s, 1H), 3.75 (s, 3H), 3.64 (br s, 1H), 3.43 (d,J=19.5 Hz, 1H), 3.16-3.07 (m, 2H), 2.84 (s, 3H), 2.64-2.57 (m, 1H),2.49-2.42 (m, 1H, partially obscured by solvent peak), 2.06 (d, J=18.0Hz, 1H), 1.66-1.51 (m, 3H), 1.49 (d, J=6.9 Hz, 3H), 1.32-1.23 (m, 28H),0.85 (t, J=6.6 Hz, 3H); ESI MS m/z 654 [C₃₉H₅₉NO₇+H]⁺; HPLC (Method A)97.4% (AUC), t_(R)=16.31 min.

Preparation of (S,Z)-2-(Oleoyloxy)propanoic acid

A solution of oleic acid (5.04 g, 17.9 mmol) and benzotriazole (2.35 g,19.8 mmol) in tetrahydrofuran (80 mL) was treated withN,N′-dicyclohexylcarbodiimide (4.13 g, 20.0 mmol) and stirred under anitrogen atmosphere for 16 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct, and the solidswere washed with diethyl ether. The combined filtrate and washings wereconcentrated. The residue was dissolved in tetrahydrofuran (75 mL) andcooled in an ice bath. The mixture was treated with (S)-lactic acid(1.62 g, 18.0 mmol) and 4-dimethylaminopyridine (2.20 g, 18.0 mmol), andthe ice bath was removed. The mixture was stirred at ambient temperatureunder a nitrogen atmosphere for 40 h. After this time, the reactionmixture was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate (250 mL) and washed with aqueous 10% citricacid (2×100 mL), water (100 mL), and brine (100 mL). The organic layerwas extracted with saturated aqueous sodium bicarbonate (2×100 mL). Thecombined aqueous bicarbonate layers were acidified to pH ˜1 with 6 Nhydrochloric acid and extracted with ethyl acetate (2×100 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was dissolved/suspendedin heptanes (100 mL), washed with aqueous 10% citric acid (50 mL) andbrine (50 mL), dried over sodium sulfate, filtered, and concentratedunder reduced pressure to provide (S,Z)-2-(oleoyloxy)propanoic acid(4.50 g, 71%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.36-5.30(m, 2H), 5.10 (q, J=5.4 Hz, 1H), 2.41-2.32 (m, 2H), 2.02-1.98 (m, 4H),1.67-1.52 (m, 5H), 1.31-1.27 (m, 20H), 0.88 (t, J=6.3 Hz, 3H), CO₂Hproton not observed.

Preparation of (S)-1-((2,5-Dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yloleate

A solution of (S,Z)-2-(oleoyloxy)propanoic acid (4.50 g, 12.7 mmol) intetrahydrofuran (60 mL) was treated with N-hydroxysuccinimide (1.58 mg,13.8 mmol) and N,N′-dicyclohexylcarbodiimide (2.91 g, 14.1 mmol) andstirred under a nitrogen atmosphere for 1.5 h. After this time, thereaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether, and the combinedfiltrate and washings were concentrated under reduced pressure toprovide (S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl oleate(6.20 g, quantitative) as an amber semi-solid: ¹H NMR (300 MHz, CDCl₃) δ5.42 (q, J=7.2 Hz, 1H), 5.36-5.32 (m, 2H), 2.84 (br s, 4H), 2.42-2.37(m, 2H), 2.02-1.98 (m, 4H), 1.72-1.53 (m, 5H), 1.30-1.27 (m, 20H), 0.88(t, J=6.3 Hz, 3H).

Preparation of(S)-1-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yloleate trifluoroacetic acid salt

A suspension of oxycodone (0.50 g, 1.6 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.8 mL, 1.8 mmol). Afteraddition was complete, the mixture was stirred under nitrogen atmospherein the ice bath for 25 min and at ambient temperature for 25 min. Thesolution was re-cooled in a dry ice/acetone bath, and the mixture wastreated with a solution of(S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl oleate (0.83 g,1.8 mmol) in tetrahydrofuran (5 mL). The temperature was allowed toslowly increase to 0° C. over 2 h. After this time, the reaction mixturewas treated with saturated aqueous ammonium chloride (50 mL) andextracted with ethyl acetate (2×50 mL). The combined organics werewashed with saturated sodium bicarbonate (50 mL) and brine (50 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by column chromatography(silica gel, 0-10% methanol/methylene chloride) followed by reversedphase column chromatography (150 g C18 column, 50-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yloleatetrifluoroacetic acid salt (343 mg, 28%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 9.23 (br s, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.75 (d,J=8.4 Hz, 1H), 6.39 (br s, 1H), 5.58-5.56 (m, 1H), 5.37-5.27 (m, 2H),5.10 (q, J=6.9 Hz, 1H), 4.99 (s, 1H), 3.75 (s, 3H), 3.68 (d, J=6.0 Hz,1H), 3.43 (d, J=19.8 Hz, 1H), 3.16-3.07 (m, 2H), 2.85 (s, 3H), 2.64-2.58(m, 1H), 2.49-2.42 (m, 1H, partially obscured by solvent peak),2.39-2.27 (m, 3H), 2.09-1.97 (m, 5H), 1.63 (d, J=11.7 Hz, 1H), 1.54-1.48(m, 5H), 1.26-1.24 (m, 20H), 0.85 (t, J=6.3 Hz, 3H); ESI MS m/z 652[C₃₉H₅₇NO₇+H]⁺; HPLC (Method A) 95.8% (AUC), t_(R)=15.64 min.

Preparation of (S)-4-tert-Butyl1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate

A suspension of oxycodone (0.500 g, 1.59 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.9 mL, 1.9 mmol). Afteraddition was complete, the mixture was stirred under a nitrogenatmosphere in the ice bath for 25 min and at ambient temperature for 25min. The solution was re-cooled in a dry ice/acetone bath, and themixture was treated with a solution of (S)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl)2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate (0.89 g, 2.0 mmol) intetrahydrofuran (5 mL). The temperature was allowed to slowly increaseto 0° C. over 2 h. After this time, the reaction mixture was treatedwith saturated aqueous ammonium chloride (50 mL) and extracted withethyl acetate (2×50 mL). The combined organics were washed withsaturated sodium bicarbonate (50 mL) and brine (50 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (150g C18 column, 5-100% acetonitrile/water) and freeze dried to provide(S)-4-tert-butyl1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate (195 mg, 19%) as a whitesolid: ESI MS m/z 644 [C₃₄H₄₅NO₁₁+H]⁺.

Preparation of(S)-3-((3-Carboxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacidtrifluoroacetic acid salt

A solution of (S)-4-tert-butyl1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate (0.195 g, 0.300 mmol) inmethylene chloride (3 mL) was treated with trifluoroacetic acid (3 mL)and stirred under at ambient temperature for 1 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas purified twice by reversed phase column chromatography (50 g C18column, 5-25% acetonitrile/water with 0.1% trifluoroacetic acid) andfreeze dried toprovide(S)-3-((3-carboxypropanoyl)oxy)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacidtrifluoroacetic acid salt (0.056 g, 35%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 12.71 (br s, 1H), 12.32 (br s, 1H), 9.17 (br s,1H), 6.85 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.30 (s, 1H), 5.59(dd, J=5.7, 1.8 Hz, 1H), 5.42 (t, J=5.4 Hz, 1H), 4.96 (s, 1H), 3.75 (s,3H), 3.65 (d, J=6.0 Hz, 1H), 3.16-3.07 (m, 3H), 2.90-2.84 (m, 5H),2.73-2.59 (m, 3H), 2.33-2.25 (m, 1H), 2.07 (d, J=18.0 Hz, 1H), 1.64 (d,J=11.4 Hz, 1H), three protons obscured by solvent peaks; ESI MS m/z 532[C₂₆H₂₉NO₁₁+H]⁺.

Preparation of (S)-1-tert-Butyl5-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)amino)pentanedioate

A suspension of oxycodone (0.450 g, 1.43 mmol) in tetrahydrofuran (6 mL)was cooled in an ice bath and treated with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (3.55 mL, 3.55 mmol). Afteraddition was complete, the mixture was stirred under nitrogen atmospherein the ice bath for 45 min and at ambient temperature for 20 min. Thesolution was re-cooled in an ice/brine bath, treated dropwise with asolution of (S)-1-tert-butyl 5-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (0.914 g, 2.28 mmol) intetrahydrofuran (6 mL), and stirred for 2 h. After this time, thereaction mixture was treated with saturated aqueous ammonium chloride(75 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganics were washed with saturated aqueous ammonium chloride (100 mL),saturated sodium bicarbonate (2×100 mL), and brine (2×100 mL); driedover sodium sulfate; filtered; and concentrated under reduced pressure.The crude residue was purified by reversed phase column chromatography(50 g C18 column, 5-100% acetonitrile/water) and freeze dried to provide(S)-1-tert-butyl5-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (0.371 g, 43%) as acolorless oil: ESI MS m/z 601 [C₃₂H₄₄N₂O₉+H]⁺.

Preparation of(S)-2-Amino-5-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-5-oxopentanoicacid bis(trifluoroacetic acid salt)

A solution of (S)-1-tert-butyl5-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (0.371 g, 0.618 mmol) inmethylene chloride (6 mL) was treated with trifluoroacetic acid (3 mL)and stirred under a nitrogen atmosphere at ambient temperature for 5 h.After this time, the reaction mixture was concentrated under reducedpressure and dried under vacuum toprovide(S)-2-amino-5-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-5-oxopentanoicacid bis(trifluoroacetic acid salt)(0.500 g, quantitative) as acolorless oil: ESI MS m/z 445 [C₂₃H₂₈N₂O₇+H]⁺.

Preparation of(S)-2-((S)-2-((tert-Butoxycarbonyl)oxy)propanamido)-5-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-5-oxopentanoicacid

Amixture(S)-2-amino-5-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-5-oxopentanoicacid bis(trifluoroacetic acid salt)(0.220 g, 0.406 mmol),(S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)oxy)propanoate(0.175 g, 0.609 mmol) and N,N-diisopropylethylamine (0.35 mL, 2.0 mmol)in methylene chloride (5 mL) was stirred at ambient temperature for 2 h.After this time, the reaction mixture was concentrated under reducedpressure togive(S)-2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-5-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-5-oxopentanoicacid (0.250 g, quantitative) as a colorless oil: ESI MS m/z 617[C₃₁H₄₀N₂O₁₁+H]⁺.

Preparation of(S)-5-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-((S)-2-hydroxypropanamido)-5-oxopentanoicacid trifluoroacetic acid salt

A solution of(S)-2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-5-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-5-oxopentanoicacid (0.250 g, 0.406) in methylene chloride (4 mL) was treated withtrifluoroacetic acid (2 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 5-25%acetonitrile/water, with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-5-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-((S)-2-hydroxypropanamido)-5-oxopentanoicacidtrifluoroacetic acid salt (0.067 g, 32%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 12.81 (br s, 1H), 9.17 (br s, 1H), 7.85 (d, J=8.1Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.27 (s, 1H),5.55-5.53 (m, 2H), 5.00 (s, 1H), 4.35-4.27 (m, 1H), 4.00 (q, J=6.9 Hz,1H), 3.75 (s, 3H), 3.64 (d, J=6.0 Hz, 1H), 3.15-3.06 (m, 2H), 2.84 (d,J=4.2 Hz, 3H), 2.73-2.55 (m, 1H), 2.32-2.24 (m, 1H), 2.14-1.89 (m, 3H),1.63 (d, J=11.4 Hz, 1H), 1.22 (d, J=6.9 Hz, 3H), four protons obscuredby solvent peaks; ESI MS m/z 517 [C₂₆H₃₂N₂O₉+H]⁺; HPLC (Method A) 96.5%(AUC), t_(R)=7.29 min.

Preparation of (S)-2-(((S)-2-Acetoxypropanoyl)oxy)-2-phenylacetic acid

(S)-Mandelic acid (553 mg, 3.63 mmol), (S)-2,5-dioxopyrrolidin-1-yl2-acetoxypropanoate (1.00 g, 4.36 mmol), 4-(dimethylamino)pyridine (44mg, 0.363 mmol), pyridine (345 mg, 4.36 mmol) and tetrahydrofuran (15mL) were combined and heated at 60° C. under a nitrogen atmosphere for48 h. After this time, the solvent was removed under reduced pressure,and the residue was partitioned between ethyl acetate (20 mL) and 10%aqueous citric acid. The organic layer was separated and extracted withsaturated aqueous sodium bicarbonate (20 ml). The aqueous phase wascollected and acidified to pH=3 with 6 N hydrochloric acid, and themixture was extracted with ethyl acetate (2×20 mL). The combinedorganics were washed with brine (50 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide(S)-2-(((S)-2-acetoxypropanoyl)oxy)-2-phenylacetic acid (1.02 g, 87%) asa colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.46-7.37 (m, 5H), 5.99 (s,1H), 5.19 (q, J=7.2 Hz, 1H), 2.12 (s, 3H), 1.61 (d, J=6.9 Hz, 3H), CO₂Hproton not observed.

Preparation of(S)—(S)-2-((2,5-Dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl2-acetoxypropanoate

A solution of (S)-2-(((S)-2-acetoxypropanoyl)oxy)-2-phenylacetic acid(1.02 g, 3.83 mmol) in tetrahydrofuran (40 mL) was treated withN-hydroxysuccinimide (485 mg, 4.21 mmol) andN,N′-dicyclohexylcarbodiimide (867 mg, 4.21 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide(S)—(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl2-acetoxypropanoate (1.65 g) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ7.56-7.51 (m, 5H), 6.38 (s, 1H), 5.17 (q, J=7.2 Hz, 1H), 2.82 (s, 4H),2.12 (s, 3H), 1.59 (d, J=6.9 Hz, 3H).

Preparation of(S)—(S)-2-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-acetoxypropanoatetrifluoroacetic acid salt

A suspension of oxycodone (0.250 g, 0.793 mmol) in tetrahydrofuran (4mL) was cooled in an ice bath and treated dropwise with a 1.0 M solutionof lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.03 mL, 1.03mmol). The mixture was stirred at 0° C. for 15 min and then treateddropwise with a solution of(S)—(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl2-acetoxypropanoate (0.374 g, 1.03 mmol) in tetrahydrofuran (4 mL). Thereaction mixture was stirred at 0° C. for 1 h. After this time, themixture was poured into saturated aqueous ammonium chloride (75 mL) andextracted with ethyl acetate (2×100 mL). The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by reversed phasechromatography (C18, 10-100% acetonitrile/water with 0.1%trifluoroacetic acid) and lyophilized to provide(S)—(S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-acetoxypropanoatetrifluoroacetic acid salt (0.120 g, 27%) as a whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 9.15 (br s, 1H), 7.59-7.54 (m, 2H),7.49-7.76 (m, 3H), 6.82 (d, J=8.4 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.30(br s, 1H), 6.22 (s, 1H), 5.53 (dd, J=6.0, 1.8 Hz, 1H), 5.15 (q, J=6.9Hz, 1H), 4.95 (s, 1H), 3.64 (s, 3H), 3.41 (d, J=19.8 Hz, 1H), 3.14-3.05(m, 2H), 2.83 (d, J=4.8 Hz, 3H), 2.70-2.53 (m, 1H), 2.46-2.38 (m, 1H),2.30-2.22 (m, 1H), 2.08 (s, 3H), 2.06-2.00 (m, 1H), 1.62 (d, J=11.1 Hz,1H), 1.53 (d, J=6.9 Hz, 3H); ESI MS m/z 564 [C₃₁H₃₃NO₉+H]⁺; HPLC (MethodA) 97.4% (AUC), t_(R)=10.24 min.

Preparation of 1-(1H-Benzo[d][1,2,3]triazol-1-yl)octadecan-1-one

A solution of stearic acid (2.00 g, 7.03 mmol) in tetrahydrofuran (30mL) was treated with 1H-benzo[d][1,2,3]triazole (921 mg, 7.73 mmol) andN,N′-dicyclohexylcarbodiimide (1.59 g, 7.73 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide1-(1H-benzo[d][1,2,3]triazol-1-yl)octadecan-1-one (3.02 g) as a whitesolid, which was used without purification.

Preparation of (S)-4-(tert-Butoxy)-4-oxo-2-(stearoyloxy)butanoic acid

(S)-4-(tert-Butoxy)-2-hydroxy-4-oxobutanoic acid (247 mg, 1.30 mmol),1-(1H-benzo[d][1,2,3]triazol-1-yl)octadecan-1-one (500 mg, 1.30 mmol),4-(dimethylamino)pyridine (159 mg, 1.30 mmol), and tetrahydrofuran (10mL) were combined and stirred at room temperature under a nitrogenatmosphere for 48 h. After this time, the solvent was removed underreduced pressure, and the residue was partitioned between ethyl acetate(30 mL) and 10% aqueous citric acid. The organic layer was separated andwashed with water (50 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (40 g silica gel column, 0-50% ethylacetate/heptane) to provide of(S)-4-(tert-butoxy)-4-oxo-2-(stearoyloxy)butanoic acid (430 mg, 72%) asa white solid: ¹H NMR (300 MHz, CDCl₃) δ 5.47 (t, J=5.7 Hz, 1H), 2.84(d, J=0.9 Hz, 2H), 2.38 (m, 2H), 1.62 (m, 2H), 1.45 (s, 9H), 1.25 (m,28H), 0.88 (t, J=6.6 Hz, 3H), CO₂H proton not observed.

Preparation of (S)-4-tert-Butyl 1-(2,5-dioxopyrrolidin-1-yl)2-(stearoyloxy)succinate

A solution of (S)-4-(tert-butoxy)-4-oxo-2-(stearoyloxy)butanoic acid(430 mg, 0.942 mmol) in tetrahydrofuran (10 mL) was treated withN-hydroxysuccinimide (119 mg, 1.04 mmol) andN,N′-dicyclohexylcarbodiimide (214 mg, 1.04 mmol) and stirred under anitrogen atmosphere for 4 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-(stearoyloxy)succinate (610 mg) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 5.76 (dd, J=8.1, 1.8 Hz, 1H),2.96 (m, 2H), 2.84 (s, 4H), 2.38 (m, 2H), 1.67 (m, 2H), 1.46 (s, 9H),1.25 (m, 28H), 0.88 (t, J=6.3 Hz, 3H).

Preparation of (S)-4-tert-Butyl1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-(stearoyloxy)succinate

A suspension of oxycodone (0.300 g, 0.95 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.24 mL,1.24 mmol).The mixture was stirred at 0° C. for 15 min and then treated dropwisewith a solution of (S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)2-(stearoyloxy)succinate (0.685 g, 1.23 mmol) in tetrahydrofuran (5 mL).The reaction mixture was stirred at 0° C. for 1 h. After this time, themixture was poured into saturated aqueous ammonium chloride (100 mL) andextracted with ethyl acetate (2×100 mL). The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by reverse phase chromatography(C18, 10-100% acetonitrile/water) and lyophilized toprovide(S)-4-tert-butyl1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-(stearoyloxy)succinate (0.390 g, 54%) as a colorless oil: ¹H NMR (300MHz, CDCl₃) δ 6.81 (d, J=8.1 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.65-5.62(m, 1H), 5.51 (t, J=6.0 Hz, 1H), 3.80-3.60 (m, 1H), 3.86 (s, 3H), 3.41(d, J=7.5 Hz, 1H), 3.24 (s, 1H), 3.21 (d, J=6.0 Hz, 1H), 2.93 (s, 3H),2.89-2.79 (m, 4H), 2.41-2.35 (m, 3H), 2.21 (d, J=17.7 Hz, 1H), 1.78 (d,J=10.5 Hz, 1H), 1.66-1.61 (m, 2H), 1.46 (s, 9H), 1.25 (br s, 30H), 0.88(t, J=6.3 Hz, 3H).

Preparation of(S)-4-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxo-3-(stearoyloxy)butanoicacidtrifluoroacetic acid salt

A solution of (S)-4-tert-butyl1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-(stearoyloxy)succinate (0.380 g, 0.504 mmol) in methylene chloride (6mL) was treated with trifluoroacetic acid (3 mL) and stirred at ambienttemperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The crude residue was purified byreversed phase chromatography (C18, 10-100% acetonitrile/water with 0.1%TFA) and freeze dried toprovide(S)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxo-3-(stearoyloxy)butanoicacidtrifluoroacetic acid salt (0.135 g, 38%) as an off-white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 12.76 (br s, 1H), 9.17 (br s, 1H), 6.84 (d,J=8.1 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 6.31 (s, 1H), 5.59 (dd, J=6.0,3.9 Hz, 1H), 5.41 (t, J=6.3 Hz, 1H), 4.96 (s, 1H), 3.75 (s, 3H), 3.65(d, J=6.3 Hz, 1H), 3.13-3.06 (m, 2H), 2.90-2.84 (m, 5H), 2.70-2.52 (m,2H), 2.33 (t, J=7.2 Hz, 2H), 2.27-2.25 (m, 1H), 1.64 (d, J=11.7 Hz, 1H),1.56-1.51 (m, 2H), 1.23 (br s, 30H), 0.88 (t, J=6.3 Hz, 3H); ESI MS m/z698 [C₁₀H₅₉NO₉+H]⁺.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl 2-acetoxypropanoate

A solution of (S)-2-acetoxypropanoic acid (10.06 g, 76.15 mmol) intetrahydrofuran (300 mL) was treated with N-hydroxysuccinimide (9.71 g,84.4 mmol) and N,N′-dicyclohexylcarbodiimide (17.36 g, 84.14 mmol) andstirred under a nitrogen atmosphere for 4.5 h. After this time, thereaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether, and the combinedfiltrate and washings were concentrated under reduced pressure. Thecrude residue was triturated with 5:1 diethyl ether/methylene chloride(120 mL). The resulting solid was isolated by filtration and washed withdiethyl ether. The combined filtrate and washings were concentratedunder reduced pressure to provide (S)-2,5-dioxopyrrolidin-1-yl2-acetoxypropanoate (18.24 g, quantitative) as an off-white foam: ¹H NMR(300 MHz, CDCl₃) δ 5.41 (t, J=7.2 Hz, 1H), 2.81 (s, 4H), 2.16 (s, 3H),1.67 (d, J=7.2 Hz, 3H).

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-acetoxypropanoate trifluoroacetic acid salt

A suspension of oxycodone (0.250 g, 0.793 mmol) in tetrahydrofuran (4mL) was cooled in an ice bath and treated dropwise with a 1.0 M solutionof lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.03 mL, 1.03mmol). The mixture was stirred at 0° C. for 15 min and then treateddropwise with a solution of (S)-2,5-dioxopyrrolidin-1-yl2-acetoxypropanoate (0.236 g, 1.03 mmol) in tetrahydrofuran (4 mL). Thereaction mixture was stirred at 0° C. for 1 h. After this time, themixture was poured into saturated aqueous ammonium chloride (100 mL) andextracted with ethyl acetate (2×100 mL). The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by reverse phase chromatography(C18, 10-25% acetonitrile/water with 0.1% trifluoroacetic acid) andlyophilized toprovide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-acetoxypropanoatetrifluoroacetic acid salt (0.095 g, 28%) as a whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 9.18 (br s, 1H), 6.86 (d, J=8.4 Hz,1H), 6.75 (d, J=8.1 Hz, 1H), 6.31 (s, 1H), 5.58 (dd, J=5.7, 1.8 Hz, 1H),5.09 (q, J=6.9 Hz, 1H), 4.99 (s, 1H), 3.76 (s, 3H), 3.65 (d, J=6.0 Hz,1H), 3.43 (d, J=20.1 Hz, 1H), 3.16-3.07 (m, 2H), 2.84 (d, J=4.8 Hz, 3H),2.72-2.52 (m, 1H), 2.49-2.43 (m, 1H, partially obscured by solventpeak), 2.29 (dd, J=18.0, 6.6 Hz, 1H), 2.10 (s, 3H), 2.30-2.22 (m, 1H),1.65 (d, J=11.4 Hz, 1H), 1.49 (d, J=6.9 Hz, 3H); ESI MS m/z 430[C₂₃H₂₇NO₇+H]⁺; HPLC (Method A) 97.8% (AUC), t_(R)=8.64 min.

Preparation of (S)-2-(((S)-2-Acetoxypropanoyl)oxy)propanoic acid

(S)-Lactic acid (472 mg, 5.24 mmol), (S)-2,5-dioxopyrrolidin-1-yl2-acetoxypropanoate (1.00 g, 4.36 mmol), 4-(dimethylamino)pyridine (53mg, 0.44 mmol), pyridine (414 mg, 5.24 mmol) and tetrahydrofuran (17 mL)were combined and heated at 80° C. under a nitrogen atmosphere for 24 h.After this time, the solvent was removed under reduced pressure, and theresidue was partitioned between ethyl acetate (20 mL) and 10% aqueouscitric acid. The organic layer was separated and extracted withsaturated aqueous sodium bicarbonate (20 ml). The aqueous phase wascollected and acidified to pH=3 with 6 N hydrochloric acid, and themixture was extracted with ethyl acetate (2×20 mL). The combinedorganics were washed with brine (50 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide(S)-2-(((S)-2-acetoxypropanoyl)oxy)propanoic acid (323 mg, 36%) as acolorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.23-5.08 (m, 2H), 2.14 (s,3H), 1.60-1.48 (m, 6H), CO₂H proton not observed.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-(((S)-2-acetoxypropanoyl)oxy)propanoate

A solution of (S)-2-(((S)-2-acetoxypropanoyl)oxy)propanoic acid (323 mg,1.58 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (200 mg, 1.74 mmol) andN,N′-dicyclohexylcarbodiimide (358 mg, 1.74 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-2,5-dioxopyrrolidin-1-yl2-(((S)-2-acetoxypropanoyl)oxy)propanoate (543 mg) as a colorless oil:¹H NMR (300 MHz, CDCl₃) δ 5.53 (q, J=5.4 Hz, 1H), 5.13 (q, J=5.4 Hz,1H), 2.85 (s, 4H), 2.13 (s, 3H), 1.72 (m, 3H), 1.57 (m, 3H).

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-acetoxypropanoyl)oxy)propanoate

A suspension of oxycodone (0.600 g, 1.90 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (2.1 mL, 2.1 mmol). Afteraddition was complete, the mixture was stirred under a nitrogenatmosphere in the ice bath for 25 min and at ambient temperature for 25min. The solution was re-cooled in a dry ice/acetone bath, and themixture was treated with a solution of (S)-2,5-dioxopyrrolidin-1-yl2-(((S)-2-acetoxypropanoyl)oxy)propanoate (0.640 g, 2.12 mmol) intetrahydrofuran (5 mL). The temperature was allowed to slowly increaseto 0° C. over 2 h. After this time, the reaction mixture was treatedwith saturated aqueous ammonium chloride (75 mL) and extracted withethyl acetate (2×100 mL). The combined organics were washed withsaturated sodium bicarbonate (75 mL) and brine (75 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (50 gC18 column, 10-100% acetonitrile/water with 0.1% trifluoroacetic acid)and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-acetoxypropanoyl)oxy)propanoate (66 mg, 5%) as a white solid:¹H NMR (300 MHz, CDCl₃) δ 9.17 (br s, 1H), 6.86 (d, J=8.1 Hz, 1H), 6.75(d, J=8.4 Hz, 1H), 6.30 (s, 1H), 5.59 (dd, J=5.7, 1.8 Hz, 1H), 5.24 (q,J=6.9 Hz, 1H), 5.07 (q, J=7.2 Hz, 1H), 4.99 (s, 1H), 3.75 (s, 3H), 3.65(d, 6.0 Hz, 1H), 3.16-3.07 (m, 2H), 2.84 (d, J=4.8 Hz, 3H), 2.72-2.58(m, 1H), 2.44-2.40 (m, 1H), 2.30 (dd, J=18.3, 6.0 Hz, 1H), 2.08 (s, 3H),2.12-2.02 (m, 1H), 1.65 (d, J=13.2 Hz, 1H), 1.53 (d, J=6.9 Hz, 3H), 1.47(d, J=6.9 Hz, 3H), one proton obscured by the solvent peaks; ESI MS m/z502 [C₂₆H₃₁NO₉+H]⁺; HPLC (Method A) 97.8% (AUC), t_(R)=8.64 min.

Preparation of(S)-4-((1-(tert-Butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoic acid

A solution of (S)-tert-butyl 2-hydroxypropanoate (3.40 g, 23.3 mmol) intetrahydrofuran (50 mL) was cooled in an ice bath and treated with a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (30.3mL, 30.3 mmol) under a nitrogen atmosphere. After 10 min, the mixturewas treated dropwise with a solution of succinic anhydride (2.80 g, 27.9mmol) in tetrahydrofuran (25 mL) and stirred at 0° C. for 45 min. Afterthis time, the reaction mixture was poured into saturated aqueousammonium chloride and extracted with ethyl acetate. The combinedorganics were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude residue was purified by columnchromatography (silica gel, 0-20% methanol/methylene chloride) andtriturated with ether, filtered, and concentrated under reduced pressureto provide (S)-4-((1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (0.600 g, 10%) as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ12.18 (br s, 1H), 4.81 (q, J=7.2 Hz, 1H), 2.51-2.49 (m, 4H, partiallyobscured by solvent peak), 1.40 (s, 9H), 1.36 (d, J=7.2 Hz, 3H).

Preparation of (S)-1-(tert-Butoxy)-1-oxopropan-2-yl(2,5-dioxopyrrolidin-1-yl) succinate

A solution of(S)-4-((1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoic acid (0.700mg, 2.84 mmol) in tetrahydrofuran (12 mL) was treated withN-hydroxysuccinimide (0.459 mg, 3.98 mmol) andN,N′-dicyclohexylcarbodiimide (0.822 mg, 3.98 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure. The crude residue was trituratedwith diethyl ether. The resulting solid was isolated by filtration andwashed with diethyl ether. The combined filtrate and washings wereconcentrated under reduced pressure to provide(S)-1-(tert-butoxy)-1-oxopropan-2-yl (2,5-dioxopyrrolidin-1-yl)succinate (0.900 g, 92%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.00(q, J=7.2 Hz, 1H), 2.99-2.96 (m, 2H), 2.85-2.80 (m, 6H), 1.48-1.45 (m,12H).

Preparation of (S)-1-(tert-Butoxy)-1-oxopropan-2-yl((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)succinate

A suspension of oxycodone (0.350 g, 1.11 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.44 mL, 1.44mmol). The mixture was stirred at 0° C. for 15 min and then treateddropwise with a solution of (S)-1-(tert-butoxy)-1-oxopropan-2-yl(2,5-dioxopyrrolidin-1-yl) succinate (0.496 g, 1.44 mmol) intetrahydrofuran (5 mL). The reaction mixture was stirred at 0° C. for 1h. After this time, the mixture was poured into saturated aqueousammonium chloride (100 mL) and extracted with ethyl acetate (2×100 mL).The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified byreverse phase chromatography (C18, 10-70% acetonitrile/water) and freezedried to provide (S)-1-(tert-butoxy)-1-oxopropan-2-yl((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)succinate (0.290 g, 48%) as a white solid: ESI MS m/z 544[C₂₉H₃₇NO₉+H]⁺.

Preparation of(S)-2-((4-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacidtrifluoroacetic acid salt

A solution of (S)-1-(tert-butoxy)-1-oxopropan-2-yl((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)succinate (0.280 g, 0.515 mmol) in methylene chloride (6 mL) was treatedwith trifluoroacetic acid (3 mL) and stirred under a nitrogen atmosphereat ambient temperature for 1 h. After this time, the reaction mixturewas concentrated under reduced pressure. The residue was purified waspurified by reversed phase column chromatography (50 g C18 column, 5-30%acetonitrile/water, with 0.1% TFA) and freeze dried toprovide(S)-2-((4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacidtrifluoroacetic acid salt (0.0200 g, 80%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 13.02 (br s, 1H), 9.18 (br s, 1H), 6.86 (d, J=8.4Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.28 (br s, 1H), 5.53 (dd, J=6.0, 1.8Hz, 1H), 4.98 (s, 1H), 4.92 (q, J=6.9 Hz, 1H), 3.75 (s, 3H), 3.64 (d,J=6.3 Hz, 1H), 3.43 (d, J=19.8 Hz, 1H), 3.15-3.06 (m, 2H), 2.84 (d,J=3.9 Hz, 3H), 2.73-2.58 (m, 5H), 2.46-2.40 (m, 1H), 2.32-2.20 (m, 1H),2.05 (d, J=18.3 Hz, 1H), 1.64 (d, J=11.1 Hz, 1H), 1.40 (d, J=6.9 Hz,3H); ESI MS m/z 488 [C₂₅H₂₉NO₉+H]⁺; HPLC (Method A) 98.9% (AUC),t_(R)=8.17 min.

Preparation of (S)-2-(((S)-2-(Oleoyloxy)propanoyl)oxy)propanoic acid

A solution of (S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yloleate (3.49 g, 7.73 mmol), (S)-lactic acid (764 mg, 8.48 mmol), and4-dimethylaminopyridine (100 mg, 0.819 mmol) in tetrahydrofuran (35 mL)was treated with pyridine (0.69 g, 8.6 mmol) and heated at 50° C. undera nitrogen atmosphere for 64 h. After this time, the reaction mixturewas cooled to room temperature and concentrated under reduced pressure.The residue was dissolved in methylene chloride (100 mL) and washed withaqueous 10% citric acid (2×50 mL). The organic layer was dried oversodium sulfate, filtered, and concentrated. The crude residue waspurified by column chromatography (silica gel, 0-10% methanol/methylenechloride) to provide (S)-2-(((S)-2-(oleoyloxy)propanoyl)oxy)propanoicacid (835 mg, 25%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ5.36-5.29 (m, 2H), 5.24-5.08 (m, 2H), 2.41-2.35 (m, 2H), 2.02-1.98 (m,4H), 1.67-1.60 (m, 2H), 1.58-1.52 (m, 6H), 1.30-1.27 (m, 20H), 0.88 (t,J=6.6 Hz, 3H), CO₂H proton not observed.

Preparation of(S)-1-(((S)-1-((2,5-Dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yloleate

A solution of (S)-2-(((S)-2-(oleoyloxy)propanoyl)oxy)propanoic acid(0.83 g, 2.0 mmol) in tetrahydrofuran (10 mL) was treated withN-hydroxysuccinimide (262 mg, 2.28 mmol) andN,N′-dicyclohexylcarbodiimide (446 mg, 2.16 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide(S)-1-(((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yloleate (1.07 g, quantitative) as a white semi-solid: ¹H NMR (300 MHz,CDCl₃) δ 5.52 (q, J=7.2 Hz, 1H), 5.38-5.33 (m, 2H), 5.11 (q, J=7.2 Hz,1H), 2.84 (br s, 4H), 2.42-2.35 (m, 2H), 2.02-1.98 (m, 4H), 1.72-1.53(m, 8H), 1.30-1.27 (m, 20H), 0.88 (t, J=6.6 Hz, 3H).

Preparation of(S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yloleate trifluoroacetic acid salt

A suspension of oxycodone (0.27 g, 0.86 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (0.9 mL, 0.9 mmol). Afteraddition was complete, the mixture was stirred under nitrogen atmospherein the ice bath for 25 min and at ambient temperature for 25 min. Thesolution was re-cooled in a dry ice/acetone bath, and the mixture wastreated with a solution of(S)-1-(((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yloleate (0.50 g, 0.95 mmol) in tetrahydrofuran (5 mL). The temperaturewas allowed to slowly increase to 0° C. over 2 h. After this time, thereaction mixture was treated with saturated aqueous ammonium chloride(50 mL) and extracted with ethyl acetate (2×50 mL). The combinedorganics were washed with saturated sodium bicarbonate (50 mL) and brine(50 mL), dried over sodium sulfate, filtered, and concentrated underreduced pressure. The crude residue was purified by reversed phasecolumn chromatography (150 g C18 column, 50-100% acetonitrile/water with0.1% trifluoroacetic acid) and freeze dried to provide(S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yloleate trifluoroacetic acid salt (176 mg, 24%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 9.22 (br s, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.75 (d,J=8.4 Hz, 1H), 6.34 (br s, 1H), 5.59-5.58 (m, 1H), 5.37-5.30 (m, 2H),5.24 (q, J=6.9 Hz, 1H), 5.08 (q, J=6.9 Hz, 1H), 4.99 (s, 1H), 3.75 (s,3H), 3.65 (br s, 1H), 3.42 (d, J=20.1 Hz, 1H), 3.15-3.06 (m, 2H), 2.84(s, 3H), 2.64-2.58 (m, 1H), 2.49-2.43 (m, 1H, partially obscured bysolvent peak), 2.37-2.26 (m, 3H), 2.09-1.95 (m, 5H), 1.63 (d, J=11.7 Hz,1H), 1.54-1.45 (m, 8H), 1.26-1.24 (m, 20H), 0.85 (t, J=6.3 Hz, 3H); ESIMS m/z 724 [C₄₂H₆₁NO₉+H]⁺; HPLC (Method A) >99% (AUC), t_(R)=15.93 min.

Preparation of (S)-2-Acetoxy-4-(tert-butoxy)-4-oxobutanoic acid

(S)-4-(tert-Butoxy)-2-hydroxy-4-oxobutanoic acid (4.88 g, 25.7 mmol),acetyl chloride (2.22 g, 28.2 mmol), N,N-diisopropylethylamine (3.99 g,30.8 mmol), and methylene chloride (200 mL) were combined at 0° C. andstirred at room temperature under a nitrogen atmosphere for 16 h. Afterthis time, 10% aqueous citric acid (100 mL) was added. The organic layerwas separated and extracted with methylene chloride (2×100 mL). Thecombined organics were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoic acid (4.59 g, 76%) as alight yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.46 (m, 1H), 2.83 (m, 2H),2.14 (s, 3H), 1.46 (s, 9H), CO₂H proton not observed.

Preparation of (S)-Di-tert-butyl 2-acetoxysuccinate

A solution of (S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoic acid (4.59 g,19.8 mmol) and tert-butanol (3.22 g, 43.5 mmol) in methylene chloride(70 mL) was treated with N,N′-dicyclohexylcarbodiimide (5.31 g, 25.7mmol) and 4-(dimethylamino)pyridine (798 mg, 6.53 mmol) at 0° C. andstirred at room temperature under a nitrogen atmosphere for 16 h. Afterthis time, the reaction mixture was filtered to remove the soliddicyclohexylurea byproduct. The solid was washed with diethyl ether (100mL), and the combined filtrate and washings were concentrated underreduced pressure. The crude residue was purified by columnchromatography (80 g silica gel column, 0-30% ethyl acetate/heptane) toprovide (S)-di-tert-butyl 2-acetoxysuccinate (3.44 g, 60%) as acolorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.30 (dd, J=7.5, 5.4 Hz, 1H),2.75 (m, 2H), 2.13 (s, 3H), 1.46 (s, 18H).

Preparation of (S)-Di-tert-butyl 2-hydroxysuccinate

(S)-Di-tert-butyl 2-acetoxysuccinate (3.44 g, 11.9 mmol), potassiumcarbonate (4.94 g, 35.8 mmol), methanol (240 mL) and water (40 mL) werecombined and stirred at 0° C. for 4 h. After this time, water (200 mL)was added, and the aqueous solution was extracted with methylenechloride (2×200 mL). The combined organics were washed with brine (50mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide (S)-di-tert-butyl 2-hydroxysuccinate (2.71 g, 92%)as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 4.30 (dd, J=10.2, 5.7 Hz,1H), 3.21 (d, J=5.4 Hz, 1H), 2.77-2.60 (m, 2H), 1.45 (s, 9H), 1.42 (s,9H).

Preparation of(S)-4-((1,4-Di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoic acid

(S)-Di-tert-butyl 2-hydroxysuccinate (428 mg, 1.74 mmol),dihydrofuran-2,5-dione (414 mg, 4.14 mmol), N,N-diisopropylethylamine(535 mg, 4.14 mmol), and methylene chloride (10 mL) were combined andstirred at room temperature under a nitrogen atmosphere for 16 h. Afterthis time, 10% aqueous citric acid (100 mL) was added. The organic layerwas separated and extracted with methylene chloride (2×50 mL). Thecombined organics were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-4-((1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoic acid(534 mg, 95%) as a brown oil: ¹H NMR (300 MHz, CDCl₃) δ 5.32 (dd, J=7.5,5.1 Hz, 1H), 2.77-2.66 (m, 6H), 1.46 (s, 18H), CO₂H proton not observed.

Preparation of (S)-Di-tert-butyl2-((4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanoyl)oxy)succinate

A solution of(S)-4-((1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoic acid(534 mg, 1.38 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (159 mg, 1.38 mmol) andN,N′-dicyclohexylcarbodiimide (284 mg, 1.38 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-di-tert-butyl2-((4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanoyl)oxy)succinate (684mg) as a brown oil: ¹H NMR (300 MHz, CDCl₃) δ 5.34 (dd, J=6.9, 5.7 Hz,1H), 3.01-2.96 (m, 2H), 2.87-2.70 (m, 8H), 1.44 (s, 18H).

Preparation of (S)-Di-tert-butyl2-((4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinate

A suspension of oxycodone (0.22 g, 0.69 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (0.8 mL, 0.8 mmol). Afteraddition was complete, the mixture was stirred under a nitrogenatmosphere in the ice bath for 25 min and at ambient temperature for 25min. The solution was re-cooled in a dry ice/acetone bath, and themixture was treated with a solution of (S)-di-tert-butyl2-((4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanoyl)oxy)succinate (0.34g, 0.77 mmol) in tetrahydrofuran (5 mL). The temperature was allowed toslowly increase to 0° C. over 2 h. After this time, the reaction mixturewas treated with saturated aqueous ammonium chloride (50 mL) andextracted with ethyl acetate (2×50 mL). The combined organics werewashed with saturated sodium bicarbonate (50 mL) and brine (50 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by reversed phase columnchromatography (50 g C18 column, 10-100% acetonitrile/water) and freezedried to provide (S)-di-tert-butyl2-((4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinate(147 mg, 33%) as a white solid: ESI MS m/z 644 [C₃₄H₄₅NO₁₁+H]⁺.

Preparation of(S)-2-((4-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid trifluoroacetic acid salt

A solution of (S)-di-tert-butyl2-((4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinate(136 mg, 0.211 mmol) in methylene chloride (4 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 7 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (C18 column, 10-70%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-2-((4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid trifluoroacetic acid salt (122 mg, 90%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 13.23 (br s, 1H), 12.59 (br s, 1H), 9.17 (br s,1H), 6.86 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.27 (s, 1H), 5.53(dd, J=6.3, 2.1 Hz, 1H), 5.22 (dd, J=7.8, 4.5 Hz, 1H), 4.99 (s, 1H),3.75 (s, 3H), 3.64 (d, J=6.3 Hz, 1H), 3.46-3.39 (m, 1H, partiallyobscured by water peak), 3.15-3.06 (m, 2H), 2.84 (s, 3H), 2.80-2.66 (m,7H), 2.49-2.43 (m, 1H, partially obscured by solvent peak), 2.27 (dd,J=17.7, 6.3 Hz, 1H), 2.06 (apparent d, J=18.0 Hz, 1H), 1.64 (d, J=11.7Hz, 1H); ESI MS m/z 532 [C₂₆H₂₉NO₁₁+H]⁺; HPLC (Method A) >99% (AUC),t_(R)=7.62 min.

Preparation of (S)-2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid

A solution of (S)-malic acid (30.28 g, 225.8 mmol) and pyridiniump-toluenesulfonate (5.16 g, 20.5 mmol) in acetone (17 mL) was cooled inan ice bath and treated with 2-methoxyprop-1-ene (85.0 mL, 888 mmol)under a nitrogen atmosphere. After 30 min, the ice bath was removed, andthe mixture was heated at 35° C. for 16 h. After this time, the reactionmixture was cooled to room temperature and concentrated under reducedpressure. The residue was dissolved in ethyl acetate (500 mL), washedwith 1:1 brine/water (4×200 mL), dried over sodium sulfate, filtered,and partially concentrated under reduced pressure to a volume ofapproximately 200 mL. The solution was treated with heptanes (200 mL)and cooled in an ice bath for 1 h. The resulting solids were isolated byfiltration and washed with heptanes toprovide(S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (23.14 g,59%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.61 (s, 1H), 4.79(dd, J=5.1, 4.8 Hz, 1H), 2.83-2.68 (m, 2H), 1.53 (s, 3H), 1.52 (s, 3H).

Preparation of (S)-Benzyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate

A solution of (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid(10.08 g, 57.88 mmol) in methylene chloride (290 mL) was treated withbenzyl alcohol (9.0 mL, 87 mmol), N,N′-dicyclohexylcarbodiimide (14.3 g,69.2 mmol), and 4-dimethylaminopyridine (2.12 g, 17.4 mmol) and stirredunder a nitrogen atmosphere for 1.5 h. After this time, the reactionmixture was filtered to remove the solid dicyclohexylurea byproduct. Thesolid was washed with methylene chloride, and the combined filtrate andwashings were concentrated under reduced pressure. The crude residue waspurified by column chromatography (silica gel, 0-20% ethylacetate/heptanes) to provide (S)-benzyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (8.63 g, 56%) as a whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.41-7.30 (m, 5H), 5.13 (dd, J=14.4,12.3 Hz, 2H), 4.87 (t, J=4.8 Hz, 1H), 3.02-2.89 (m, 2H), 1.52 (s, 3H),1.49 (s, 3H).

Preparation of (S)-4-(Benzyloxy)-2-hydroxy-4-oxobutanoic acid

A solution of (S)-benzyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate(8.63 g, 32.7 mmol) in acetic acid (50 mL) and water (25 mL) was heatedat 60° C. for 1.5 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in waterand freeze dried to provide (S)-4-(benzyloxy)-2-hydroxy-4-oxobutanoicacid (7.32 g, quantitative) as a white solid: ¹H NMR (300 MHz, DMSO-d₆)δ 12.57 (br s, 1H), 7.40-7.29 (m, 5H), 5.57 (br s, 1H), 5.11 (s, 2H),4.33 (dd, J=7.8, 4.8 Hz, 1H), 2.77 (dd, J=15.6, 4.8 Hz, 1H), 2.61 (dd,J=15.6, 7.8 Hz, 1H); ESI MS m/z 223 [C₁₁H₁₂O₅−H]⁻.

Preparation of (S)-2-Acetoxy-4-(benzyloxy)-4-oxobutanoic acid

A solution of (S)-4-(benzyloxy)-2-hydroxy-4-oxobutanoic acid (3.00 g,13.4 mmol) in methylene chloride (15 mL) was treated with acetic acid (3mL) and cooled in an ice bath under a nitrogen atmosphere. The solutionwas treated dropwise with acetyl chloride (1.05 mL, 14.8 mmol). After 15min, the ice bath was removed, and the mixture was stirred at ambienttemperature for 16 h. After this time, the reaction mixture wasconcentrated under reduced pressure and dried under vacuum to provide(S)-2-acetoxy-4-(benzyloxy)-4-oxobutanoic acid (4.12 g, quantitative) asa colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 7.39-7.33 (m, 5H), 5.25(dd, J=8.1, 4.5 Hz, 1H), 5.14 (dd, J=14.4, 12.6 Hz, 2H), 3.00 (dd,J=16.5, 4.5 Hz, 1H), 2.89 (dd, J=16.5, 8.1 Hz, 1H), 2.02 (s, 3H), CO₂Hproton not observed.

Preparation of (S)-4-Benzyl 1-tert-butyl 2-acetoxysuccinate

A solution of (S)-2-acetoxy-4-(benzyloxy)-4-oxobutanoic acid (3.57 g,13.4 mmol) in methylene chloride (60 mL) was treated with tert-butanol(4.5 mL, 47 mmol), N,N′-dicyclohexylcarbodiimide (4.30 g, 20.8 mmol),and 4-dimethylaminopyridine (462 mg, 3.78 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (silica gel, 0-20% ethyl acetate/heptanes) toprovide (S)-4-benzyl 1-tert-butyl 2-acetoxysuccinate (2.78 g, 64%) as acolorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 7.42-7.30 (m, 5H), 5.19-5.14(m, 3H), 3.00-2.85 (m, 2H), 2.03 (s, 3H), 1.37 (s, 9H).

Preparation of (S)-3-Acetoxy-4-(tert-butoxy)-4-oxobutanoic acid

A solution of (S)-4-benzyl 1-tert-butyl 2-acetoxysuccinate (1.02 g, 3.16mmol) in ethanol (30 mL) was sparged with nitrogen gas for 30 min. Thesolution was treated with 5% palladium on carbon (214 mg) and spargedwith hydrogen gas for 5 min. The mixture was stirred under a hydrogenatmosphere for 2 h. After this time, the reaction mixture was spargedwith nitrogen gas for 5 min and filtered through diatomaceous earth. Thefiltrate was concentrated under reduced pressure to provide(S)-3-acetoxy-4-(tert-butoxy)-4-oxobutanoic acid (731 mg, 99%) as acolorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 12.74 (br s, 1H), 5.10 (dd,J=8.1, 4.8 Hz, 1H), 2.81-2.64 (m, 2H), 2.06 (s, 3H), 1.40 (s, 9H).

Preparation of (S)-1-tert-Butyl 4-(2,5-dioxopyrrolidin-1-yl)2-acetoxysuccinate

A solution of (S)-3-acetoxy-4-(tert-butoxy)-4-oxobutanoic acid (725 mg,3.12 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (396 mg, 3.44 mmol) andN,N′-dicyclohexylcarbodiimide (709 mg, 3.44 mmol) and stirred under anitrogen atmosphere for 6 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide (S)-1-tert-butyl4-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (1.25 g, quantitative)as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 5.28 (dd, J=7.5, 4.8Hz, 1H), 3.39-3.22 (m, 2H), 2.82 (s, 4H), 2.08 (s, 3H), 1.41 (s, 9H).

Preparation of (S)-1-tert-Butyl4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate

A suspension of oxycodone (0.52 g, 1.7 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.8 mL, 1.8 mmol). Afteraddition was complete, the mixture was stirred under nitrogen atmospherein the ice bath for 25 min and at ambient temperature for 25 min. Thesolution was re-cooled in a dry ice/acetone bath, and the mixture wastreated with a solution of (S)-1-tert-butyl 4-(2,5-dioxopyrrolidin-1-yl)2-acetoxysuccinate (0.60 g, 1.8 mmol) in tetrahydrofuran (5 mL). Thetemperature was allowed to slowly increase to 0° C. over 2 h. After thistime, the reaction mixture was treated with saturated aqueous ammoniumchloride (50 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organics were washed with saturated sodium bicarbonate (50 mL)and brine (50 mL), dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude residue was purified by reversed phasecolumn chromatography (150 g C18 column, 10-100% acetonitrile/water) andfreeze dried to provide (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate (232 mg, 27%) as a white solid: ESI MS m/z 530[C₂₈H₃₅NO₉+H]⁺.

Preparation of(S)-2-Acetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate (230 mg, 0.434 mmol) in methylene chloride (4 mL) wastreated with trifluoroacetic acid (1 mL) and stirred under a nitrogenatmosphere at ambient temperature for 3 h. After this time, the reactionmixture was concentrated under reduced pressure. The residue waspurified by reversed phase column chromatography (50 g C18 column,10-70% acetonitrile/water with 0.1% trifluoroacetic acid) and freezedried to provide(S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid 2,2,2-trifluoroacetatetrifluoroacetic acid salt (225 mg, 88%) as afluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 13.38 (br s, 1H), 9.17(br s, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.29 (s,1H), 5.56 (dd, J=5.7, 1.8 Hz, 1H), 5.26 (dd, J=8.4, 4.2 Hz, 1H), 4.99(s, 1H), 3.74 (s, 3H), 3.65 (d, J=6.3 Hz, 1H), 3.43 (d, J=20.1 Hz, 1H,partially obscured by water peak), 3.16-3.06 (m, 3H), 2.98 (dd, J=16.8,8.4 Hz, 1H), 2.84 (apparent d, J=3.9 Hz, 3H), 2.65-2.57 (m, 1H),2.49-2.42 (m, 1H, partially obscured by solvent peak), 2.28 (dd, J=17.7,6.3 Hz, 1H), 2.09 (s, 3H), 2.09-2.04 (m, 1H), 1.65 (d, J=11.1 Hz, 1H);ESI MS m/z 474 [C₂₄H₂₇NO₉+H]⁺; HPLC (Method A) 96.7% (AUC), t_(R)=7.78min.

Preparation of (S)-tert-Butyl 2-acetoxy-2-phenylacetate

A mixture of (S)-2-acetoxy-2-phenylacetic acid (22.0 g, 104 mmol) andtert-butanol (19.0 g, 257 mmol) in methylene chloride (150 mL) at 0° C.was treated with N,N′-dicyclohexylcarbodiimide (28.0 g, 136 mmol). Afterstirring for 1 h, the ice bath was removed and the reaction mixture wasstirred at ambient temperature for 18 h. After this time, the mixturewas filtered and the filtrate was concentrated under reduced pressure.The residue was purified by column chromatography (330 g silica gelcolumn, 5-20% ethyl acetate/heptane) to provide (S)-tert-butyl2-acetoxy-2-phenylacetate (14.4 g, 52%): ¹H NMR (300 MHz, CDCl₃) δ7.48-7.43 (m, 2H), 7.40-7.35 (m, 3H), 5.80 (s, 1H), 2.18 (s, 3H), 1.40(s, 9H).

Preparation of (S)-tert-Butyl 2-hydroxy-2-phenylacetate

A solution of (S)-tert-butyl 2-acetoxy-2-phenylacetate (14.4 g, 54.1mmol) in methanol (15 mL) was cooled to 0° C. and treated with asolution of sodium bicarbonate (22.5 g, 163 mmol) in water/methanol(3:2, 145 mL). The reaction mixture was stirred at 0° C. for 2 h, andthen neutralized by addition of citric acid (10 g, 52 mmol). The mixturewas partially concentrated under reduced pressure and then extractedwith methylene chloride. The organic layer was washed with water andbrine, dried over sodum sulfate, filtered, and concentrated underreduced pressure to provide (S)-tert-butyl 2-hydroxy-2-phenylacetate(11.2 g), which was used without purification: ¹H NMR (300 MHz, CDCl₃) δ7.43-7.29 (m, 5H), 5.03 (d, J=6.0 Hz, 1H), 3.50 (d, J=6.0 Hz, 1H), 1.41(s, 9H).

Preparation of(S)-4-(2-(tert-Butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoic acid

A solution of (S)-tert-butyl 2-hydroxy-2-phenylacetate (3.15 g, 15.1mmol) in tetrahydrofuran (35 mL) at 0° C. was treated with a 1.0 Msolution of lithium bis(trimethylsilyl)amidein tetrahydrofuran (16 mL,16 mmol), and the mixture was stirred for 10 min. After this time, asolution of succinic anhydride (1.33 g, 16.6 mmol) in tetrahydrofuran(25 mL) was added, and the mixture was stirred at 0° C. for 1.5 h. Afterthis time, the mixture was poured into a saturated solution of ammoniumchloride and extracted with ethyl acetate. The organic extract was driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide (S)-4-(2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (4.60 g): ESI MS m/z 634 [C₁₆H₂₀O₆+NH₄]⁺.

Preparation of (S)-2-(tert-Butoxy)-2-oxo-1-phenylethyl(2,5-dioxopyrrolidin-1-yl) succinate

A mixture of (S)-4-(2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (4.60 g, 15.0 mmol) and N-hydroxysuccinimide (1.90 g, 16.5 mmol) intetrahydrofuran (75 mL) at 0° C. was treated withN,N-dicyclohexylcarbodiimide (3.40 g, 16.5 mmol). The ice bath wasremoved, and the reaction mixture was stirred at ambient temperature for4 h. After this time, diethyl ether (75 mL) was added, and the mixturewas filtered. The filtrate was concentrated under reduced pressure toprovide (S)-2-(tert-butoxy)-2-oxo-1-phenylethyl(2,5-dioxopyrrolidin-1-yl) succinate (10.0 g) that was used withoutpurification: ¹H NMR (300 MHz, CDCl₃) δ 7.47-7.42 (m, 2H), 7.42-7.35 (m,3H), 5.84 (s, 1H), 3.06-2.98 (m, 2H), 2.93-2.88 (m, 2H), 2.83 (s, 4H),1.39 (s, 9H).

Preparation of (S)-2-(tert-Butoxy)-2-oxo-1-phenylethyl((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)succinate

A suspension of oxycodone (530 mg, 1.68 mmol) in tetrahydrofuran (9 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (2.0 mL, 2.0 mmol).After addition was complete, the mixture was stirred under nitrogenatmosphere in the ice bath for 10 min and at ambient temperature for 5min. The solution was re-cooled in a dry ice/acetone bath, and themixture was treated dropwise with a solution of(S)-2-(tert-butoxy)-2-oxo-1-phenylethyl (2,5-dioxopyrrolidin-1-yl)succinate (810 mg, 2.00 mmol) in tetrahydrofuran (7 mL). After additionwas complete, the dry ice/acetone bath was replaced with a wet ice/brinebath, and the mixture was stirred for 20 min. After this time, thereaction mixture was treated with saturated aqueous ammonium chloride(50 mL) and extracted with ethyl acetate (2×50 mL). The combinedorganics were washed with saturated sodium bicarbonate (50 mL), water(50 mL), and brine (50 mL); dried over sodium sulfate; filtered; andconcentrated under reduced pressure. The crude residue was purified byreversed phase column chromatography (150 g C18 column, 20-100%acetonitrile/water) and freeze dried to provide(S)-2-(tert-butoxy)-2-oxo-1-phenylethyl((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)succinate (344 mg, 34%) as a white solid: ESI MS m/z 606 [C₃₄H₃₉NO₉+H]⁺.

Preparation of(S)-2-((4-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt

A solution of (S)-2-(tert-butoxy)-2-oxo-1-phenylethyl((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)succinate (340 mg, 0.561 mmol) in methylene chloride (8 mL) was treatedwith trifluoroacetic acid (2 mL) and stirred under a nitrogen atmosphereat ambient temperature for 5 h. After this time, the reaction mixturewas concentrated under reduced pressure. The residue was purified byreversed phase column chromatography (150 g C18 column, 10-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-2-((4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt (338 mg, 91%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 13.29 (br s, 1H), 9.18 (br s, 1H), 7.46-7.40 (m,5H), 6.86 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.29 (br s, 1H),5.84 (s, 1H), 5.50-5.46 (m, 1H), 4.96 (s, 1H), 3.74 (s, 3H), 3.64 (d,J=6.0 Hz, 1H), 3.43 (d, J=19.8 Hz, 1H), 3.15-3.06 (m, 2H), 2.84(apparent d, J=3.3 Hz, 3H), 2.76 (s, 4H), 2.65-2.58 (m, 1H), 2.43 (dd,J=12.9, 4.2 Hz, 1H), 2.26 (dd, J=17.7, 6.0 Hz, 1H), 2.04 (apparent d,J=17.7 Hz, 1H), 1.63 (d, J=12.0 Hz, 1H); ESI MS m/z 550 [C₃₀H₃₁NO₉+H]⁺;HPLC (Method A) >99% (AUC), t_(R)=9.29 min.

Preparation of (S)-2-Acetoxy-2-phenylacetic acid

A solution of (S)-2-hydroxy-2-phenylacetic acid (16.4 g, 108 mmol) inacetic acid (30 mL) and water (1.3 mL) at 0° C. was treated dropwisewith acetyl chloride (23.0 mL, 32.4 mmol). The reaction mixture wasstirred at 0° C. for 1 h and then at room temperature for 18 h. Afterthis time, the mixture was concentrated under reduced pressure, and theresidue was dissolved in ethyl acetate, washed with water and brine,dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide (S)-2-acetoxy-2-phenylacetic acid (22.0 g, 97%): ¹HNMR (300 MHz, CDCl₃) δ 7.50-7.45 (m, 2H), 7.42-7.37 (m, 3H), 5.94 (s,1H), 2.20 (s, 3H), CO₂H proton not observed.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl 2-acetoxy-2-phenylacetate

A mixture of (S)-2-acetoxy-2-phenylacetic acid (6.50 g, 31.0 mmol) andN-hydroxysuccinimide (4.00 g, 34.8 mmol) in tetrahydrofuran (150 mL) at0° C. was added N,N′-dicyclohexylcarbodiimide (7.00 g, 33.9 mmol). Theice bath was removed, and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (100 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide (S)-2,5-dioxopyrrolidin-1-yl2-acetoxy-2-phenylacetate (10.0 g) that was used without purification:¹H NMR (300 MHz, CDCl₃) δ 7.57-7.52 (m, 2H), 7.46-7.43 (m, 3H), 6.33 (s,1H), 2.80 (s, 4H), 2.20 (s, 3H).

Preparation of (S)-2-((S)-2-Acetoxy-2-phenylacetoxy)propanoic acid

A mixture of (S)-2,5-dioxopyrrolidin-1-yl 2-acetoxy-2-phenylacetate(3.40 g, 11.6 mmol), (S)-2-hydroxypropanoic acid (1.30 g, 14.4 mmol),pyridine (1.1 mL, 13.6 mmol), and 4-dimethylaminopyridine (100 mg, 0.8mmol) in tetrahydrofuran (50 mL) was stirred at reflux for 18 h. Afterthis time, the mixture was cooled to room temperature, partiallyconcentrated under reduced pressure, diluted with ethyl acetate, andwashed with 10% citric acid. The organic layer was extracted withsaturated sodium bicarbonate. The aqueous extract was carefully treatedwith 2N hydrochloric acid until acidic by pH paper analysis, and thenextracted with ethyl acetate. The organic extracts were dried oversodium carbonate, filtered and concentrated. The residue was purified byreversed phase column chromatography (150 g C18 column, 5-100%acetonitrile/water) to provide(S)-2-((S)-2-acetoxy-2-phenylacetoxy)propanoic acid (1.15 g, 37%): ESIMS m/z 531 [2×(C₁₃H₁₄O₆)−H]⁻.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-((S)-2-acetoxy-2-phenylacetoxy)propanoate

A mixture of (S)-2-((S)-2-acetoxy-2-phenylacetoxy)propanoic acid (1.15g, 4.32 mmol) and N-hydroxysuccinimide (545 mg, 4.74 mmol) intetrahydrofuran (20 mL) was treated with N,N′-dicyclohexylcarbodiimide(975 mg, 4.74 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (20 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide (S)-2,5-dioxopyrrolidin-1-yl2-((S)-2-acetoxy-2-phenylacetoxy)propanoate (1.64 g) that was usedwithout purification: ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.46 (m, 2H),7.42-7.35 (m, 3H), 5.99 (s, 1H), 5.49 (q, J=7.1 Hz, 1H), 2.79 (s, 4H),2.19 (s, 3H), 1.68 (d, J=7.1 Hz, 3H).

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-acetoxy-2-phenylacetoxy)propanoate trifluoroacetic acid salt

A suspension of oxycodone (0.50 g, 1.6 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.8 mL, 1.8 mmol). Afteraddition was complete, the mixture was stirred under nitrogen atmospherein the ice bath for 25 min and at ambient temperature for 25 min. Thesolution was re-cooled in a dry ice/acetone bath, and the mixture wastreated with a solution of (S)-2,5-dioxopyrrolidin-1-yl2-((S)-2-acetoxy-2-phenylacetoxy)propanoate (0.67 g, 1.8 mmol) intetrahydrofuran (5 mL). The temperature was allowed to slowly increaseto 0° C. over 2 h. After this time, the reaction mixture was treatedwith saturated aqueous ammonium chloride (50 mL) and extracted withethyl acetate (2×50 mL). The combined organics were washed withsaturated sodium bicarbonate (50 mL) and brine (50 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (150g C18 column, 30-100% acetonitrile/water with 0.1% trifluoroacetic acid)and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-acetoxy-2-phenylacetoxy)propanoate trifluoroacetic acid salt(190 mg, 18%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.19 (br s,1H), 7.52-7.48 (m, 2H), 7.42-7.37 (m, 3H), 6.86 (d, J=8.4 Hz, 1H), 6.75(d, J=8.1 Hz, 1H), 6.28 (s, 1H), 6.06 (s, 1H), 5.47 (dd, J=5.7, 1.8 Hz,1H), 5.28 (q, J=6.9 Hz, 1H), 4.82 (s, 1H), 3.73 (s, 3H), 3.64 (d, J=6.0Hz, 1H), 3.42 (d, J=20.1 Hz, 1H), 3.15-3.06 (m, 2H), 2.84 (apparent d,J=4.8 Hz, 3H), 2.68-2.57 (m, 1H), 2.49-2.35 (m, 1H, partially obscuredby solvent peak), 2.27 (dd, J=18.0, 6.0 Hz, 1H), 2.14 (s, 3H), 2.04(apparent d, J=17.7 Hz, 1H), 1.62 (d, J=12.0 Hz, 1H), 1.48 (d, J=6.9 Hz,3H); ESI MS m/z 564 [C₃₁H₃₃NO₉+H]⁺; HPLC (Method A) 98.2% (AUC),t_(R)=10.19 min.

Preparation of (R)-2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-1-yl)acetic acid

A solution of (R)-malic acid (4.50 g, 33.6 mmol), 2-methoxyprop-1-ene(9.68 g, 134 mmol) and pyridinium p-toluenesulfonate (844 mg, 3.36 mmol)in acetone (50 mL) was stirred at 35° C. for 16 h. After this time,water (200 mL) was added, and the aqueous solution was extracted withethyl acetate (2×200 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas recrystallized from ethyl acetate/heptane to provide(R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (2.92 g, 50%) asan off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 4.72 (dd, J=6.6, 3.9 Hz,1H), 3.01 (dd, J=17.4, 3.9 Hz, 1H), 2.86 (dd, J=17.4, 6.6 Hz, 1H), 1.63(s, 3H), 1.58 (s, 3H), CO₂H proton not observed.

Preparation of (R)-tert-Butyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate

A solution of (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid(2.92 g, 16.8 mmol) and tert-butanol (1.86 g, 25.2 mmol) in methylenechloride (40 mL) was treated with N,N′-dicyclohexylcarbodiimide (4.16 g,20.2 mmol) and 4-(dimethylamino)pyridine (616 mg, 5.04 mmol) and stirredat room temperature under a nitrogen atmosphere for 4 h. After thistime, the reaction mixture was filtered to remove the soliddicyclohexylurea byproduct. The solid was washed with diethyl ether (100mL), and the combined filtrate and washings were concentrated underreduced pressure. The crude residue was purified by columnchromatography (80 g silica gel column, 0-30% ethyl acetate/heptane) toprovide (R)-tert-butyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate(3.19 g, 82%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 4.66 (dd,J=6.0, 3.9 Hz, 1H), 2.84 (dd, J=17.1, 4.2 Hz, 1H), 2.72 (dd, J=16.8, 6.3Hz, 1H), 1.63 (s, 3H), 1.56 (s, 3H), 1.47 (s, 9H).

Preparation of (R)-4-(tert-Butoxy)-2-hydroxy-4-oxobutanoic acid

A solution of (R)-tert-butyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (3.19 g, 13.9 mmol) inacetic acid (21 mL) and water (9 mL) was stirred at 60° C. for 4 h.After this time, the solvent was removed under reduced pressure. Theresidue was dried under vacuum to provide(R)-4-(tert-butoxy)-2-hydroxy-4-oxobutanoic acid (2.81 g) as a colorlessoil: ¹H NMR (300 MHz, DMSO-d₆) δ 4.48 (dd, J=5.7, 5.4 Hz, 1H), 2.83 (m,2H), 1.48 (m, 9H), CO₂H and OH protons not observed.

Preparation of (R)-2-Acetoxy-4-(tert-butoxy)-4-oxobutanoic acid

(R)-4-(tert-Butoxy)-2-hydroxy-4-oxobutanoic acid (2.81 g, 14.8 mmol),acetyl chloride (1.28 g, 16.3 mmol), N,N-diisopropylethylamine (5.74 g,44.4 mmol), and methylene chloride (150 mL) were combined at 0° C. andthen stirred at room temperature under a nitrogen atmosphere for 4 h.After this time, 10% aqueous citric acid (100 mL) was added. The organiclayer was separated and extracted with methylene chloride (2×100 mL).The combined organics were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(R)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoic acid (3.44 g) as a blackoil, which was used without purification.

Preparation of (R)-Di-tert-butyl 2-acetoxysuccinate

A solution of (R)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoic acid (3.44 g,14.8 mmol) and tert-butanol (2.41 g, 32.6 mmol) in methylene chloride(70 mL) was treated with N,N′-dicyclohexylcarbodiimide (3.69 g, 19.2mmol) and 4-(dimethylamino)pyridine (597 mg, 4.88 mmol) and stirred atroom temperature under a nitrogen atmosphere for 16 h. After this time,the reaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether (100 mL), and thecombined filtrate and washings were concentrated under reduced pressure.The crude residue was purified by column chromatography (80 g silica gelcolumn, 0-30% ethyl acetate/heptane) to provide (R)-di-tert-butyl2-acetoxysuccinate (1.70 g, 40%) as a colorless oil: ¹H NMR (300 MHz,CDCl₃) δ 5.30 (dd, J=7.5, 5.4 Hz, 1H), 2.75 (m, 2H), 2.12 (s, 3H), 1.46(s, 18H).

Preparation of (R)-Di-tert-butyl 2-hydroxysuccinate

(R)-Di-tert-butyl 2-acetoxysuccinate (1.70 g, 5.90 mmol), potassiumcarbonate (2.44 g, 17.7 mmol), methanol (90 mL) and water (15 mL) werecombined and stirred at 0° C. for 3 h. After this time, water (200 mL)was added, and the aqueous solution was extracted with methylenechloride (2×200 mL). The combined organics were washed with brine (50mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide (R)-di-tert-butyl 2-hydroxysuccinate (1.16 g, 80%)as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 4.30 (dd, J=10.2, 5.7 Hz,1H), 3.19 (d, J=5.4 Hz, 1H), 2.75-2.66 (m, 2H), 1.47 (s, 9H), 1.45 (s,9H).

Preparation of(R)-4-((1,4-Di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoic acid

(R)-Di-tert-butyl 2-hydroxysuccinate (1.16 g, 4.71 mmol),dihydrofuran-2,5-dione (1.41 g, 14.1 mmol), N,N-diisopropylethylamine(1.82 g, 14.1 mmol), and methylene chloride (30 mL) were combined andstirred at room temperature under a nitrogen atmosphere for 16 h. Afterthis time, 10% aqueous citric acid (100 mL) was added. The organic layerwas separated and extracted with methylene chloride (2×50 mL). Thecombined organics were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(R)-4-((1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoic acid(2.05 g) as a brown oil: ¹H NMR MHz, CDCl₃) δ 5.32 (dd, J=7.5, 5.1 Hz,1H), 2.77-2.66 (m, 6H), 1.45 (s, 18H), CO₂H proton not observed.

Preparation of (R)-Di-tert-butyl2-((4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanoyl)oxy)succinate

A solution of(R)-4-((1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoic acid(2.05 g, 5.92 mmol) in tetrahydrofuran (60 mL) was treated withN-hydroxysuccinimide (681 mg, 5.92 mmol) andN,N′-dicyclohexylcarbodiimide (1.22 g, 5.92 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (R)-di-tert-butyl2-((4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanoyl)oxy)succinate (2.75g) as a brown oil: ¹H NMR (300 MHz, CDCl₃) δ 5.34 (dd, J=6.9, 5.7 Hz,1H), 3.01-2.96 (m, 2H), 2.87-2.70 (m, 8H), 1.45 (s, 18H).

Preparation of (R)-Di-tert-butyl2-((4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinate

A suspension of oxycodone (500 mg, 1.59 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (1.8 mL, 1.8 mmol). Afteraddition was complete, the mixture was stirred at −50° C. for 45 min.The mixture was treated dropwise with a solution of (R)-di-tert-butyl2-((4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanoyl)oxy)succinate (775mg, 1.80 mmol) in tetrahydrofuran (8 mL). After addition was complete,the mixture was stirred at −50° C. for 30 min. After this time, thereaction mixture was treated with saturated aqueous ammonium chloride(20 mL) and extracted with ethyl acetate (3×20 mL). The combinedorganics were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude residue was purified by reversed phasecolumn chromatography (50 g C18 column, 10-100% acetonitrile/water) andfreeze dried to provide (R)-di-tert-butyl2-((4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinate(144 mg, 15%) as a white solid: ESI MS m/z 644 [C₃₄H₄₅NO₁₁+H]⁺.

Preparation of(R)-2-((4-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid

A solution of (R)-di-tert-butyl2-((4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinate(144 mg, 0.220 mmol) in methylene chloride (1 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. This material was purified byreversed phase column chromatography (50 g C18 column, 5-40%acetonitrile/water) and freeze dried to provide(R)-2-((4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid (102 mg, 86%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 6.81(d, J=8.1 Hz, 1H), 6.70 (d, J=8.1 Hz, 1H), 5.53 (dd, J=5.7, 2.1 Hz, 1H),5.09-5.06 (m, 1H), 4.93 (s, 1H), 3.74 (s, 3H), 3.28 (d, J=18.9 Hz, 1H),2.83-2.61 (m, 9H), 2.37-2.13 (m, 6H), 2.02 (d, J=18 Hz, 1H), 1.52 (d,J=9.9 Hz, 1H), two CO₂H and OH protons not observed; ESI MS m/z 530[C₂₆H₂₉NO₁₁+H]⁺; HPLC (Method A) >99% (AUC), t_(R)=7.64 min.

Preparation of (S)-4-Benzyl 1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)2-hydroxysuccinate

A solution of (S)-tert-butyl 2-hydroxypropanoate (1.11 g, 7.61 mmol) intetrahydrofuran (15 mL) was cooled in an ice bath and treated dropwisewith a 1.0 M solution of lithium bis(trimethylsilyl)amide intetrahydrofuran (7.6 mL, 7.6 mmol). After addition was complete, themixture was stirred at ambient temperature for 15 min. The mixture wasre-cooled in the ice bath and treated dropwise with a solution of(S)-benzyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (2.01 g, 7.61mmol) in tetrahydrofuran 10 mL). After addition was complete, themixture was stirred at 0° C. for 4 h. After this time, the reactionmixture was treated with saturated aqueous ammonium chloride (10 mL) andextracted with ethyl acetate (2×25 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (silica gel,0-30% ethyl acetate/heptanes) to provide (S)-4-benzyl1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl) 2-hydroxysuccinate (0.89, 33%)as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.38-7.35 (m, 5H), 5.17(d, J=1.0 Hz, 1H), 5.05 (dd, J=14.1, 8.4 Hz, 1H), 4.69-4.53 (m, 1H),3.15 (dd, J=18.0, 6.0 Hz, 1H), 3.02 (dd, J=15.9, 3.9 Hz, 1H), 2.90-2.80(m, 1H), 1.46 (d, J=8.1 Hz, 3H), 1.45 (s, 9H), OH proton not observed.

Preparation of (S)-4-Benzyl 1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate

(S)-4-Benzyl 1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl) 2-hydroxysuccinate(1.86 g, 5.28 mmol), di-tert-butyl dicarbonate (1.38 g, 6.34 mmol), andN,N-dimethylpyridin-4-amine (64 mg, 0.53 mmol) were combined and stirredin methylene chloride (60 mL) at ambient temperature for 3 h. After thistime, the mixture was concentrated under reduced pressure. The cruderesidue was purified by column chromatography (silica gel, 0-30% ethylacetate/heptanes) to provide (S)-4-benzyl1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate (1.91 g, 80%) as a colorless oil:¹H NMR (300 MHz, CDCl₃) δ 7.38-7.33 (m, 5H), 5.41 (dd, J=9.6, 3.3 Hz,1H), 5.21 (d, J=12.3 Hz, 1H), 5.13 (d, J=12.3 Hz, 1H), 5.02 (dd, J=14.1,3.6 Hz, 1H), 3.12 (dd, J=17.8, 3.6 Hz, 1H), 2.95 (dd, J=18.1, 8.1 Hz,1H), 1.49 (s, 9H), 1.45 (d, J=6.2 Hz, 3H), 1.44 (s, 9H).

Preparation of(S)-4-(((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)oxy)-3-((tert-butoxycarbonyl)oxy)-4-oxobutanoicacid

A solution of (S)-4-benzyl 1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate (0.27 g, 0.60 mmol) in ethylalcohol (5 mL) was treated with palladium on carbon (10%, 30 mg). Themixture was stirred with under a hydrogen atmosphere at ambienttemperature for 2 h. After this time, the reaction mixture was filteredand concentrated under reduced pressure to provide(S)-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-3-((tert-butoxycarbonyl)oxy)-4-oxobutanoicacid (0.22 g, 99%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.38(dd, J=9.3, 3.6 Hz, 1H), 5.05 (dd, J=14.1, 6.9 Hz, 1H), 3.13 (dd,J=17.1, 3.3 Hz, 1H), 2.95 (dd, J=17.1, 9.3 Hz, 1H), 1.50 (s, 9H), 1.47(d, J=6.2 Hz, 3H), 1.46 (s, 9H), CO₂H proton not observed.

Preparation of (S)-1-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate

(S)-4-(((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)oxy)-3-((tert-butoxycarbonyl)oxy)-4-oxobutanoicacid (0.21 g, 0.58 mmol), 1-hydroxypyrrolidine-2,5-dione (77 mg, 0.67mmol) and dicyclohexylcarbodiimide (0.13 g, 0.64 mmol) were combined andstirred in tetrahydrofuran (4 mL) at ambient temperature for 4 h. Afterthis time, the mixture was filtered and concentrated under reducedpressure to provide (S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate (0.3g, 99%) as a sticky solid: ¹H NMR (300 MHz, CDCl₃) δ 5.45 (dd, J=9.6,3.3 Hz, 1H), 5.05 (dd, J=14.1, 6.9 Hz, 1H), 3.46 (dd, J=17.1, 3.3 Hz,1H), 3.18 (dd, J=17.1, 9.3 Hz, 1H), 2.87-2.82 (m, 4H), 1.50 (s, 9H),1.47 (d, J=6.2 Hz, 3H), 1.46 (s, 9H).

Preparation of (S)-1-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate

A suspension of oxycodone (500 mg, 1.59 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (1.8 mL, 1.8 mmol). Afteraddition was complete, the mixture was stirred at −50° C. for 45 min.The mixture was treated dropwise with a solution of(S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate (800mg, 1.8 mmol) in tetrahydrofuran (8 mL). After addition was complete,the mixture was stirred at −50° C. for 30 min. After this time, thereaction mixture was treated with saturated aqueous ammonium chloride(20 mL) and extracted with ethyl acetate (3×20 mL). The combinedorganics were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude residue was purified by reversed phasecolumn chromatography (50 g C18 column, 10-100% acetonitrile/water) andfreeze dried to provide (S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate (77 mg, 7%) as a white solid: ESIMS m/z 660 [C₃₄H₄₅NO₁₂+H]⁺.

Preparation of(S)-2-(((S)-2-Hydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacid

A solution of (S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate (77 mg, 0.12 mmol) in methylenechloride (1 mL) was treated with trifluoroacetic acid (1 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 1 h. After thistime, the reaction mixture was concentrated under reduced pressure. Thismaterial was purified by reversed phase column chromatography (50 g C18column, 5-40% acetonitrile/water) and freeze dried to provide(S)-2-(((S)-2-hydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacid (34 mg, 58%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 6.75 (d,J=8.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 5.91 (s, 1H), 5.52 (dd, J=5.7,2.4 Hz, 1H), 4.95 (dd, J=13.8, 6.9 Hz, 1H), 4.86 (s, 1H), 4.49-4.47 (m,1H), 3.74 (s, 3H), 3.13 (d, J=18.9 Hz, 1H), 2.97-2.89 (m, 2H), 2.69-2.61(m, 2H), 2.46-2.42 (m, 1H), 2.28-2.22 (m, 2H), 2.12-2.00 (m, 4H),1.42-1.38 (m, 4H), CO₂H and OH protons not observed; ESI MS m/z 504[C₂₅H₂₉NO₁₀+H]⁺; HPLC (Method A) >99% (AUC), t_(R)=7.58 min.

Preparation of(S)-2-(((S)-3-Acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic acid

A solution of (S)-1-tert-butyl 4-(2,5-dioxopyrrolidin-1-yl)2-acetoxysuccinate g, 4.44 mmol), lactic acid (447 mg, 4.96 mmol), and4-dimethylaminopyridine (57 mg, 0.47 mmol) in tetrahydrofuran (30 mL)was treated with pyridine (0.72 g, 8.9 mmol) and heated at 50° C. undera nitrogen atmosphere for 48 h. After this time, the reaction mixturewas cooled to room temperature and concentrated under reduced pressure.The residue was dissolved in ethyl acetate (50 mL) and washed withaqueous 10% citric acid (2×25 mL) and water (25 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The cruderesidue was purified by column chromatography (silica gel, 0-10%methanol/methylene chloride) to(S)-2-(((S)-3-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic (455mg, 34%) as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 13.07 (br s,1H), 5.17 (dd, J=7.8, 4.8 Hz, 1H), 4.96 (q, J=6.9 Hz, 1H), 2.98-2.83 (m,2H), 2.05 (s, 3H), 1.41 (s, 9H), 1.39 (d, J=6.9 Hz, 3H).

Preparation of (S)-1-tert-Butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate

A solution of(S)-2-(((S)-3-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic (450mg, 1.48 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (185 mg, 1.61 mmol) andN,N′-dicyclohexylcarbodiimide (338 mg, 1.64 mmol) and stirred under anitrogen atmosphere for 7 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide (S)-1-tert-butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate (703 mg, quantitative) as an off-white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 5.52 (q, J=6.9 Hz, 1H), 5.18 (dd, J=7.5, 5.1 Hz,1H), 3.05-2.91 (m, 2H), 2.82 (br s, 4H), 2.05 (s, 3H), 1.56 (d, J=6.9Hz, 3H), 1.41 (s, 9H).

Preparation of (S)-1-tert-Butyl4-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate

A suspension of oxycodone (415 mg, 1.32 mmol) in tetrahydrofuran (6 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.4 mL, 1.4 mmol).After stirring at 0° C. for 45 min, the ice bath was replaced with a dryice/acetonitrile bath (−45° C.). The mixture was treated dropwise with asolution of (S)-1-tert-butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate (590 mg, 1.47 mmol) in tetrahydrofuran (7 mL) andstirred for 1 h. After this time, the dry ice/acetonitrile bath wasreplaced with a wet ice/brine bath, and the reaction mixture was treatedwith saturated aqueous ammonium chloride (50 mL) and extracted withethyl acetate (2×50 mL). The combined organics were washed withsaturated sodium bicarbonate (50 mL) and brine mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The cruderesidue was purified by reversed phase column chromatography (50 g C18column, 10-100% acetonitrile/water) and freeze dried to provide(S)-1-tert-butyl4-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate (241 mg, 30%) as a fluffy white solid: ¹H NMR (300MHz, DMSO-d₆) δ 6.73 (d, J=8.4 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 5.55(dd, J=5.4, 2.4 Hz, 1H), 5.21-5.13 (m, 2H), 4.83 (s, 1H), 4.72 (s, 1H),3.73 (s, 3H), 3.10 (d, J=18.6 Hz, 1H), 2.97-2.94 (m, 2H), 2.83 (d, J=6.0Hz, 1H), 2.60 (dd, J=18.9, 6.0 Hz, 1H), 2.41 (dd, J=11.4, 3.9 Hz, 1H),2.31 (s, 3H), 2.22 (dd, J=12.6, 4.8 Hz, 1H), 2.10-1.94 (m, 3H), 2.04 (s,3H), 1.49 (d, J=6.9 Hz, 3H) 1.41 (s, 9H), 1.39 (d, J=12.3 Hz, 1H); ESIMS m/z 602 [C₃₁H₃₉NO₁₁+H]⁺; HPLC (Method A) 96.6% (AUC), t_(R)=10.46min.

Preparation of(S)-2-Acetoxy-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of (S)-1-tert-butyl4-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate (196 mg, 0.326 mmol) in methylene chloride (4 mL) wastreated with trifluoroacetic acid (1 mL) and stirred under a nitrogenatmosphere at ambient temperature for 5 h. After this time, the reactionmixture was concentrated under reduced pressure. The residue waspurified by reversed phase column chromatography (C18 column, 10-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-2-acetoxy-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (164 mg, 76%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) 13.37 (br s, 1H), 9.18 (br s, 1H), 6.85 (d, J=8.4Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.30 (s, 1H), 5.59 (dd, J=5.7, 1.8 Hz,1H), 5.27 (dd, J=7.8, 4.5 Hz, 1H), 5.18 (q, J=7.2 Hz, 1H), 5.00 (s, 1H),3.75 (s, 3H), 3.65 (d, J=6.3 Hz, 1H), 3.43 (d, J=19.8 Hz, 1H, partiallyobscured by water peak), 3.16-3.07 (m, 2H), 3.05-2.90 (m, 2H), 2.84(apparent d, J=3.0 Hz, 3H), 2.66-2.55 (m, 1H), 2.49-2.43 (m, 1H,partially obscured by solvent peak), 2.34-2.26 (m, 1H), 2.10-2.04 (m,1H), 2.04 (s, 3H), 1.65 (d, J=11.1 Hz, 1H), 1.50 (d, J=7.2 Hz, 3H); ESIMS m/z 546 [C₂₇H₃₁NO₁₁+H]⁺; HPLC (Method A) 99.0% (AUC), t_(R)=8.48 min.

Preparation of(2R,3R)-2,3-Diacetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A suspension of oxycodone (252 mg, 0.799 mmol) in tetrahydrofuran (6 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (0.85 mL, 0.85 mmol). Afterstirring in the ice bath under a nitrogen atmosphere for 1 h, themixture was treated with solid (3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyldiacetate (268 mg, 1.24 mmol). After 30 min, the ice bath was removed,and the mixture was stirred at ambient temperature for 30 min. Afterthis time, the reaction mixture was re-cooled in an ice bath, treatedwith a 1:1 mixture of trifluoroacetic acid/acetonitrile (0.5 mL), andconcentrated under reduced pressure. The crude residue was purified byreversed phase column chromatography (50 g C18 column, 10-60%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(2R,3R)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (113 mg, 27%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 13.87 (br s, 1H), 9.17 (br s, 1H), 6.88 (d, J=8.4Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.34 (s, 1H), 5.77 (d, J=3.0 Hz, 1H),5.68 (d, J=3.0 Hz, 1H), 5.56 (dd, J=6.3, 2.1 Hz, 1H), 4.88 (s, 1H), 3.76(s, 3H), 3.65 (d, J=6.3 Hz, 1H), 3.43 (d, J=20.1 Hz, 1H), 3.16-3.07 (m,2H), 2.84 (apparent d, J=3.3 Hz, 3H), 2.64-2.57 (m, 1H), 2.49-2.43 (m,1H, partially obscured by solvent peak), 2.33-2.25 (m, 1H), 2.18 (s,3H), 2.14 (s, 3H), 2.11-2.05 (m, 1H), 1.65 (d, J=11.4 Hz, 1H); ESI MSm/z 532 [C₂₆H₂₉NO₁₁+H]⁺; HPLC (Method A) 94.2% (AUC), t_(R)=7.90 min.

Preparation of(S)-2-(((S)-2-Acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid

(S)-Mandelic acid (770 mg, 5.06 mmol), (S)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (2.00 g, 6.07 mmol),4-(dimethylamino)pyridine (62 mg, 0.506 mmol), pyridine (480 mg, 6.07mmol) and tetrahydrofuran (34 mL) were combined and heated at 60° C.under a nitrogen atmosphere for 24 h. After this time, the solvent wasremoved under reduced pressure, and the residue was participated betweenethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer wasseparated and extracted with saturated aqueous sodium bicarbonate (20ml). The aqueous phase was collected and acidified to pH=3 with 6 Nhydrochloric acid, and the mixture was extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(S)-2-(((S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid (754 mg, 41%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ7.48-7.39 (m, 5H), 6.03 (s, 1H), 5.54 (m, 1H), 3.01-2.76 (m, 2H), 2.13(s, 3H), 1.45 (s, 9H), CO₂H proton not observed.

Preparation of (S)-4-tert-Butyl1-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate

A solution of(S)-2-(((S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid (754 mg, 2.06 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (260 mg, 2.26 mmol) andN,N′-dicyclohexylcarbodiimide (466 mg, 2.26 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-4-tert-butyl1-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate (930 mg) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ7.55-7.43 (m, 5H), 6.39 (s, 1H), 5.53 (m, 1H), 2.98-2.76 (m, 6H), 2.15(s, 3H), 1.46 (s, 9H).

Preparation of (S)-4-tert-Butyl1-((S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate

A suspension of oxycodone (286 mg, 1.59 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (1.0 mL, 1.0 mmol). Afteraddition was complete, the mixture was stirred at −50° C. for 45 min.The mixture was treated dropwise with a solution of (S)-4-tert-butyl1-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate (0.47 g, 1.0 mmol) in tetrahydrofuran (8 mL). Afteraddition was complete, the mixture was stirred at −50° C. for 30 min.After this time, the reaction mixture was treated with saturated aqueousammonium chloride (20 mL) and extracted with ethyl acetate (3×20 mL).The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (50 g C18 column, 10-100% acetonitrile/water) andfreeze dried to provide (S)-4-tert-butyl1-((S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate (89 mg, 15%) as a white solid: ESI MS m/z 602[C₃₆H₄₁NO₁₁+H]⁺.

Preparation of(S)-3-Acetoxy-4-((S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of (S)-4-tert-butyl1-((S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate (89 mg, 0.13 mmol) in methylene chloride (1 mL) wastreated with trifluoroacetic acid (1 mL) and stirred under a nitrogenatmosphere at ambient temperature for 1 h. After this time, the reactionmixture was concentrated under reduced pressure. This material waspurified by reversed phase column chromatography (50 g C18 column, 5-40%acetonitrile/water) and freeze dried to provide(S)-3-acetoxy-4-((S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacidtrifluoroacetic acid salt mg, 57%) as a white solid: ¹H NMR (300MHz, DMSO-d6; Mixture of diastereomers) δ 7.58-7.53 (m, 2H), 7.48-7.44(m, 3H), 6.75-6.71 (m, 0.8H), 6.69-6.64 (m, 1.2H), 6.21 (s, 0.4H), 6.12(s, 0.6H), 5.53-5.47 (m, 0.8H), 5.45-5.43 (m, 1.2H), 4.81 (s, 0.6H),4.78 (s, 0.4H), 3.70 (s, 1.8H), 3.60 (s, 1.2H), 3.12 (d, J=18.3 Hz, 1H),3.00-3.72 (m, 5H), 2.46-2.42 (m, 1H), 2.35 (s, 3H), 2.28-1.99 (m, 6H),1.38 (d, J=12.6 Hz, 1H), CO₂H, CF₃CO₂H, and OH protons not observed; ESIMS m/z 608 [C₃₂H₃₃NO₁₁+H]⁺; HPLC (Method A) 90.7% (AUC), t_(R)=9.40 min.

Preparation of(S)-3-acetoxy-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid

A solution of (S)-2,5-dioxotetrahydrofuran-3-yl acetate (0.70 g, 3.4mmol) and (S)-tert-butyl 2-hydroxypropanoate (0.50 g, 3.4 mmol) inN,N-dimethylformamide (4 mL) was cooled in an ice bath and treated withpyridine (0.36 mL, 4.4 mmol). After addition was complete, the mixturewas stirred at ambient temperature for 16 h. After this time, themixture was diluted with water (20 mL) and extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(S)-3-acetoxy-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (0.6 g, 58%) as a brown oil: ¹H NMR (300 MHz, CDCl₃) ¹H NMR (300MHz, CDCl₃) δ 5.49 (dd, J=9.3, 3.3 Hz, 1H), 5.03 (dd, J=14.1, 6.9 Hz,1H), 3.13 (dd, J=17.1, 3.3 Hz, 1H), 2.95 (dd, J=17.1, 9.3 Hz, 1H), 2.13(s, 3H), 1.48 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), CO₂H proton not observed.

Preparation of (S)-1-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate

(S)-3-Acetoxy-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (1.8 g, 6.01 mmol), 1-hydroxypyrrolidine-2,5-dione (0.81 g, 7.0mmol) and dicyclohexylcarbodiimide (1.36 g, 6.61 mmol) were combined andstirred in tetrahydrofuran (40 mL) at ambient temperature for 4 h. Afterthis time, the mixture was filtered and concentrated under reducedpressure to provide (S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (2.64 g, 99%) as asticky solid: ¹H NMR (300 MHz, DMSO-d₆) δ 5.50 (dd, J=8.7, 4.2 Hz, 1H),5.00 (dd, J=14.1, 6.9 Hz, 1H), 3.40 (dd, J=17.1, 3.3 Hz, 1H), 3.30 (dd,J=17.1, 9.3 Hz, 1H), 2.77 (s, 4H), 2.10 (s, 3H), 1.46 (d, J=6.9 Hz, 3H),1.41 (s, 9H).

Preparation of (S)-1-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate

A suspension of oxycodone (500 mg, 1.59 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (1.8 mL, 1.8 mmol). Afteraddition was complete, the mixture was stirred at −50° C. for 45 min.The mixture was treated dropwise with a solution of(S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)1-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (700 mg, 1.81 mmol) intetrahydrofuran (8 mL). After addition was complete, the mixture wasstirred at −50° C. for 30 min. After this time, the reaction mixture wastreated with saturated aqueous ammonium chloride (20 mL) and extractedwith ethyl acetate (3×20 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (50 gC18 column, 10-100% acetonitrile/water) and freeze dried to provide(S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate (110 mg, 11%) as a white solid: ESI MS m/z 602[C₃₁H₃₉NO₁₁+H]⁺.

Preparation of(S)-2-(((S)-2-Acetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt

A solution of (S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate (110 mg, 0.171 mmol) in methylene chloride (1 mL) wastreated with trifluoroacetic acid (1 mL) and stirred under a nitrogenatmosphere at ambient temperature for 1 h. After this time, the reactionmixture was concentrated under reduced pressure. This material waspurified by reversed phase column chromatography (50 g C18 column, 5-40%acetonitrile/water) and freeze dried to provide(S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacidtrifluoroacetic acid salt (66 mg, 71%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 6.81 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 5.57(dd, J=5.7, 2.1 Hz, 1H), 5.39 (dd, J=9.6, 3.2 Hz, 1H), 5.04 (dd, J=14.1,6.9 Hz, 1H), 4.95 (s, 1H), 3.73 (s, 3H), 3.29-3.26 (m, 1H), 3.17 (d,J=17.1 Hz, 1H), 3.00-2.72 (m, 3H), 2.64-2.62 (m, 3H), 2.39-2.37 (m, 3H),2.22-2.00 (m, 2H), 2.11 (s, 3H), 1.53 (d, J=9.9 Hz, 1H), 1.43 (d, J=6.9Hz, 3H), CO₂H, CF₃CO₂H, and OH protons not observed; ESI MS m/z 546[C₂₇H₃₁NO₁₁+H]⁺.

Preparation of (S)-tert-Butyl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate

(S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (30 g, 11 mmol),(S)-lactic acid (1.0 g, 11 mmol), N,N-dimethylpyridin-4-amine (0.13 g,0.11 mmol) and pyridine (1.16 mL, 12.5 mmol) were combined intetrahydrofuran (50 mL) and heated at 60° C. for 72 h. After this time,the reaction mixture was treated with saturated aqueous ammoniumchloride (10 mL) and extracted with ethyl acetate (2×25 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide(S)-2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoicacid (2.0 g, 99%) as a yellow oil.

(S)-2-(2-((S)-2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoicacid (2.0 g, 8.1 mmol), tert-butyl alcohol (0.90 g, 12mmol),N,N-dimethylpyridin-4-amine (0.30 g, 2.4 mmol) anddicyclohexylcarbodiimide (2.0 g, 9.7 mmol) were combined and stirred inmethylene chloride (60 mL) at ambient temperature for 16 h. After thistime, the mixture was concentrated under reduced pressure. The cruderesidue was purified by column chromatography (silica gel, 0-30% ethylacetate/heptanes) to provide (S)-tert-butyl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate (0.4g, 16%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 4.99 (dd, J=14.1,6.9 Hz, 1H), 4.74 (dd, J=6.6, 3.6 Hz, 1H), 3.04 (dd, J=17.4, 3.6 Hz,1H), 2.84 (dd, J=14.1, 6.6 Hz, 1H), 1.62 (s, 3H), 1.56 (s, 3H), 1.47 (d,J=7.2 Hz, 3H), 1.46 (s, 9H).

Preparation of(S)-4-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)oxy)-2-hydroxy-4-oxobutanoicacid

A solution of (S)-tert-butyl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate (0.50g, 1.7 mmol), acetic acid (3 mL) and water (1 mL) was heated at 60° C.for 1 h. After this time, the mixture was concentrated under reducedpressure. The residue was diluted with toluene and concentrated underreduced pressure to provide(S)-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-2-hydroxy-4-oxobutanoicacid (0.5 g, 99%) as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 12.6(s, 1H), 5.51 (s, 1H), 4.82 (dd, J=14.1, 6.9 Hz, 1H), 4.31-4.30 (m, 1H),2.72 (dd, J=15.9, 4.5 Hz, 1H), 2.60 (dd, J=15.9, 7.8 Hz, 1H), 1.40 (s,9H), 1.36 (d, J=7.2 Hz, 3H).

Preparation of(S)-2-Acetoxy-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid

A solution of(S)-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-2-hydroxy-4-oxobutanoicacid (0.43 g, 1.6 mmol) in methylene chloride (3 mL) in a cold bath wastreated dropwise with acetyl chloride (0.13 mL, 1.8 mmol) and stirred atambient temperature for 16 h. After this time, the mixture wasconcentrated under reduced pressure to provide(S)-2-acetoxy-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (0.6 g, 99%) as a clear oil: ¹H NMR (300 MHz, DMSO-d₆) δ 13.3 (s,1H), 5.25 (dd, J=7.8, 4.8 Hz, 1H), 4.89 (dd, J=14.1, 7.2 Hz, 1H),2.97-2.89 (m, 2H), 2.05 (s, 3H), 1.40 (s, 9H), 1.37 (d, J=6.9 Hz, 3H).

Preparation of (S)-4-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)1-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate

(S)-2-acetoxy-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (0.50 g, 1.6 mmol), 1-hydroxypyrrolidine-2,5-dione (0.22 g, 1.9mmol) and dicyclohexylcarbodiimide (0.37 g, 1.8 mmol) were combined andstirred in tetrahydrofuran (10 mL) at ambient temperature for 4 h. Afterthis time, the mixture was filtered and concentrated under reducedpressure to provide (S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate (0.3g, 99%) as a sticky oil: ¹H NMR (300 MHz, DMSO-d₆) δ 5.76 (dd, J=7.8,4.8 Hz, 1H), 4.90 (dd, J=14.1, 7.2 Hz, 1H), 3.21-3.12 (m, 2H), 2.82 (s,4H), 2.12 (s, 3H), 1.41 (s, 9H), 1.38 (d, J=6.9 Hz, 3H).

Preparation of (S)-4-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate

A suspension of oxycodone (470 mg, 1.59 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (1.7 mL, 1.7 mmol). Afteraddition was complete, the mixture was stirred at −50° C. for 45 min.The mixture was treated dropwise with a solution of(S)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)1-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (775 mg, 1.80 mmol) intetrahydrofuran (8 mL). After addition was complete, the mixture wasstirred at −50° C. for 30 min. After this time, the reaction mixture wastreated with saturated aqueous ammonium chloride (20 mL) and extractedwith ethyl acetate (3×20 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (50 gC18 column, 10-100% acetonitrile/water) and freeze dried to provide(S)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate (140 mg, 12%) as a white solid: ESI MS m/z 602[C₃₁H₃₉NO₁₁+H]⁺.

Preparation of(S)-2-(((S)-3-Acetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt

A solution of (S)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate (0.14 g, 0.23 mmol) in methylene chloride (1 mL) wastreated with trifluoroacetic acid (1 mL) and stirred under a nitrogenatmosphere at ambient temperature for 1 h. After this time, the reactionmixture was concentrated under reduced pressure. This material waspurified by reversed phase column chromatography (50 g C18 column, 5-40%acetonitrile/water) and freeze dried to provide(S)-2-(((S)-3-acetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacidtrifluoroacetic acid salt (79 mg, 63%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 6.77 (d, J=8.4 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H), 5.61(dd, J=5.7, 2.4 Hz, 1H), 5.45 (dd, J=6.9, 2.1 Hz, 1H), 4.99 (dd, J=14.1,6.9 Hz, 1H), 4.87 (s, 1H), 3.74 (s, 3H), 3.19 (d, J=19.2 Hz, 1H),3.12-2.99 (m, 5H), 2.79-2.59 (m, 2H), 2.47-2.46 (m, 1H), 2.37-1.97 (m,7H), 1.45 (d, J=12.6 Hz, 1H), 1.40 (d, J=7.2 Hz, 3H), CO₂H, CF₃CO₂H, andOH protons not observed; ESI MS m/z 546 [C₂₇H₃₁NO₁₁+H]⁺.

Preparation of(S)-2-(((S)-2-Acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic acid

(S)-Lactic acid (109 mg, 1.21 mmol), (S)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (400 mg, 1.21 mmol),4-(dimethylamino)pyridine (15 mg, 0.121 mmol), pyridine (115 mg, 1.45mmol) and tetrahydrofuran (8 mL) were combined and heated at 60° C.under a nitrogen atmosphere for 24 h. After this time, the solvent wasremoved under reduced pressure, and the residue was partitioned betweenethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer wasseparated and extracted with saturated aqueous sodium bicarbonate (20ml). The aqueous phase was collected and acidified to pH=3 with 6 Nhydrochloric acid, and the mixture was extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(S)-2-(((S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic acid(247 mg, 67%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.47 (m,1H), 5.21 (m, 1H), 2.95-2.77 (m, 2H), 2.13 (s, 3H), 1.56 (d, J=6.9 Hz,3H), 1.45 (s, 9H), CO₂H proton not observed.

Preparation of (S)-4-tert-Butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate

A solution of(S)-2-(((S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic acid(247 mg, 0.812 mmol) in tetrahydrofuran (10 mL) was treated withN-hydroxysuccinimide (103 mg, 0.893 mmol) andN,N′-dicyclohexylcarbodiimide (184 mg, 0.893 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-4-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate (384 mg) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ5.38-5.45 (m, 2H), 2.97-2.81 (m, 6H), 2.12 (s, 3H), 1.71 (q, J=6.9 Hz,3H), 1.46 (s, 9H).

Preparation of (S)-4-tert-Butyl1-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate

A suspension of oxycodone (500 mg, 1.59 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.8 mL, 1.8 mmol).After addition was complete, the mixture was stirred at −50° C. for 45min. The mixture was treated dropwise with a solution of(S)-4-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate (1.0 g, 1.8 mmol) in tetrahydrofuran (8 mL). Afteraddition was complete, the mixture was stirred at −50° C. for 30 min.After this time, the reaction mixture was treated with saturated aqueousammonium chloride (20 mL) and extracted with ethyl acetate (3×20 mL).The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified byreversed phase column chromatography (50 g C18 column, 10-100%acetonitrile/water) and freeze dried to provide (S)-4-tert-butyl1-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate (420 mg, 45%) as a white solid: ESI MS m/z 602[C₃₁H₃₉NO₁₁+H]⁺.

Preparation of(S)-3-Acetoxy-4-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of (S)-4-tert-butyl1-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate (120 mg, 0.2 mmol) in methylene chloride (1 mL) wastreated with trifluoroacetic acid (1 mL) and stirred under a nitrogenatmosphere at ambient temperature for 1 h. After this time, the reactionmixture was concentrated under reduced pressure. This material waspurified by reversed phase column chromatography (50 g C18 column, 5-40%acetonitrile/water) and freeze dried to provide(S)-3-acetoxy-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacidtrifluoroacetic acid salt (69 mg, 63%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 12.8 (s, 1H), 9.19 (s, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.76(d, J=8.1 Hz, 1H), 6.31 (s, 1H), 5.59 (dd, J=6.0, 1.8 Hz, 1H), 5.36 (dd,J=9.0, 3.6 Hz, 1H), 5.26 (dd, J=14.1, 6.9 Hz, 1H), 5.00 (s, 1H), 3.75(s, 3H), 3.65 (d, J=6.3 Hz, 1H), 3.43 (d, J=20.1 Hz, 1H), 3.16-3.07 (m,2H), 2.96-2.72 (m, 5H), 2.62-2.52 (m, 1H), 2.46-2.42 (m, 1H), 2.34-2.26(m, 1H), 2.09 (s, 3H), 2.06 (d, J=16.0 Hz, 1H), 1.64 (d, J=11.1 Hz, 1H),1.52 (d, J=6.9 Hz, 3H); ESI MS m/z 546 [C₂₇H₃₁NO₁₁+H]⁺.

Preparation of(2R,3R)-2,3-Diacetoxy-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid and(2R,3R)-2,3-Diacetoxy-4-((R)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid

A solution of (3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate (1.35g, 6.25 mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. was treatedwith (S)-tert-butyl 2-hydroxy-2-phenylacetate (˜7:3 SIR mixture, 1.02 g,4.90 mmol) followed by pyridine (0.36 mL, 4.47 mmol), and the mixturewas stirred at 0° C. for 1 h. After this time, the reaction mixture wasdiluted with ethyl acetate; washed with 10% citric acid, water, andbrine; filtered; and concentrated. The residue was purified by reversedphase column chromatography (150 g C18 column, 3-20% acetonitrile/water)to provide(2R,3R)-2,3-diacetoxy-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (dr 95:5, 1.47 g, 54%) and(2R,3R)-2,3-diacetoxy-4-((R)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (dr 85:15, 0.55 g, 18%).

(2R,3R)-2,3-Diacetoxy-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid: ¹H NMR (300 MHz, CDCl₃) δ 7.26 (s, 5H), 5.94 (s, 1H), 5.90 (d,J=2.6 Hz, 1H), 5.81 (s, J=2.6 Hz, 1H), 2.17 (s, 3H), 1.92 (s, 3H), 1.40(s, 9H), CO₂H proton not observed.

(2R,3R)-2,3-Diacetoxy-4-((R)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid: ¹H NMR (300 MHz, CDCl₃) δ 7.38 (s, 5H), 5.99 (d, J=2.6 Hz, 1H),5.81 (d, J=2.6 Hz, 1H), 5.79 (s, 1H), 2.25 (s, 3H), 2.21 (s, 3H), 2.51(s, 9H), CO₂H proton not observed.

Preparation of (2R,3R)-1-((S)-2-(tert-Butoxy)-2-oxo-1-phenylethyl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate

A mixture of(2R,3R)-2,3-diacetoxy-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (1.07 g, 2.52 mmol) and N-hydroxysuccinimide (320 mg, 2.78 mmol) intetrahydrofuran (14 mL) was treated with N,N′-dicyclohexylcarbodiimide(570 mg, 2.76 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (20 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide(2R,3R)-1-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (1.41 g, 80%) thatwas used without purification: ¹H NMR (300 MHz, CDCl₃) δ 7.38 (s, 5H),6.14 (d, J=2.8 Hz, 1H), 6.02 (d, J=2.8 Hz, 1H), 5.92 (s, 1H), 2.83 (s,4H), 2.24 (s, 3H), 1.97 (s, 3H), 1.41 (s, 9H).

Preparation of (2R,3R)-1-((S)-2-(tert-Butoxy)-2-oxo-1-phenylethyl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate

A suspension of oxycodone (500 mg, 1.59 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.8 mL, 1.8 mmol).After addition was complete, the mixture was stirred at −50° C. for 45min. The mixture was treated dropwise with a solution of(2R,3R)-1-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (900 mg, 1.80 mmol)in tetrahydrofuran (8 mL). After addition was complete, the mixture wasstirred at −50° C. for 30 min. After this time, the reaction mixture wastreated with saturated aqueous ammonium chloride (15 mL) and extractedwith ethyl acetate (3×15 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (50 gC18 column, 10-100% acetonitrile/water) and freeze dried to provide(2R,3R)-1-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (280 mg, 24%) as a white solid: ESI MS m/z 722[C₃₈H₄₃NO₁₃+H]⁺.

Preparation of(S)-2-(((2R,3R)-2,3-Diacetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt

A solution of (2R,3R)-1-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (0.15 g, 0.21 mmol) in methylene chloride (1 mL)was treated with trifluoroacetic acid (1 mL) and stirred under anitrogen atmosphere at ambient temperature for 1 h. After this time, thereaction mixture was concentrated under reduced pressure. This materialwas purified by reversed phase column chromatography (50 g C18 column,5-40% acetonitrile/water) and freeze dried to provide(S)-2-(((2R,3R)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylaceticacidtrifluoroacetic acid salt (96 mg, 69%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 13.5 (s, 1H), 9.18 (s, 1H), 7.46-7.41 (m, 5H), 6.88 (d,J=8.4 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.35 (s, 1H), 6.01 (s, 1H), 5.92(dd, J=24.6, 2.7 Hz, 1H), 5.55 (dd, J=6.0, 2.1 Hz, 1H), 4.87 (s, 1H),3.75 (s, 3H), 3.65 (d, J=6.0 Hz, 1H), 3.43 (d, J=20.1 Hz, 1H), 3.16-3.07(m, 2H), 2.84 (d, J=3.6 Hz, 3H), 2.64-2.61 (m, 1H), 2.41-2.32 (m, 2H),2.32-2.27 (m, 1H), 2.20 (s, 3H), 2.08 (d, J=18.3 Hz, 1H), 2.00 (s, 3H),1.64 (d, J=11.7 Hz, 1H); ESI MS m/z 666 [C₃₄H₃₅NO₁₃+H]⁺.

Preparation of(2S,3S)-2,3-Diacetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A suspension of oxycodone (270 mg, 0.856 mmol) in tetrahydrofuran (7 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (0.90 mL, 0.90 mmol). After30 min, the mixture was treated with solid(3S,4S)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate (338 mg, 1.56 mmol)and stirred in the ice bath under a nitrogen atmosphere for 2.5 h. Afterthis time, the reaction mixture was treated with trifluoroacetic acid(0.3 mL) and concentrated under reduced pressure. The crude residue waspurified by reversed phase column chromatography (50 g C18 column,10-60% acetonitrile/water with 0.1% trifluoroacetic acid) and freezedried to provide(2S,3S)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (219 mg, 40%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 13.87 (br s, 1H), 9.18 (br s, 1H), 6.84 (d, J=8.4Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.33 (s, 1H), 5.80 (d, J=3.0 Hz, 1H),5.59 (dd, J=5.7, 1.8 Hz, 1H), 5.56 (d, J=3.0 Hz, 1H), 5.00 (s, 1H), 3.72(s, 3H), 3.65 (d, J=6.3 Hz, 1H), 3.43 (d, J=19.8 Hz, 1H), 3.16-3.07 (m,2H), 2.84 (apparent d, J=2.7 Hz, 3H), 2.65-2.58 (m, 1H), 2.49-2.43 (m,1H, partially obscured by solvent peak), 2.34-2.25 (m, 1H), 2.17 (s,3H), 2.15 (s, 3H), 2.11-2.05 (m, 1H), 1.66 (d, J=10.8 Hz, 1H); ESI MSm/z 532 [C₂₆H₂₉NO₁₁+H]⁺; HPLC (Method A) 98.3% (AUC), t_(R)=7.91 min.

Preparation of (S)-4-(tert-Butoxy)-3-hydroxy-4-oxobutanoic acid

A solution of (S)-3-acetoxy-4-(tert-butoxy)-4-oxobutanoic acid (3.58 g,15.4 mmol) in methanol (80 mL) was cooled in an ice bath and treatedwith a chilled solution potassium carbonate (4.71 g, 34.1 mmol) in water(40 mL). The mixture was stirred in the ice bath for 6 h. After thistime, the reaction mixture was treated with aqueous 10% citric acid (200mL) to a pH of approximately 3-4 and concentrated under reduced pressureto remove the volatiles. The aqueous mixture was extracted withmethylene chloride (4×100 mL). The aqueous mixture was then furtheracidified to pH ˜2 with 6 N hydrochloric acid and extracted again withmethylene chloride (8×100 mL). The combined organics from allextractions were dried over sodium sulfate, filtered, and concentratedunder reduced pressure to provide(S)-4-(tert-butoxy)-3-hydroxy-4-oxobutanoic acid (2.44 g, 84%) as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.27 (br s, 1H), 5.46 (brs,1H), 4.19 (dd, J=7.5, 5.4 Hz, 1H), 2.57 (dd, J=15.6, 5.4 Hz, 1H), 2.43(dd, J=15.6, 7.5 Hz, 1H), 1.41 (s, 9H).

Preparation of(S)-4-(tert-Butoxy)-3-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)-4-oxobutanoicacid

A solution of (S)-4-(tert-butoxy)-3-hydroxy-4-oxobutanoic acid (955 mg,5.02 mmol) in tetrahydrofuran (12 mL) was cooled in an ice bath under anitrogen atmosphere and treated with a solution of(S)-1-(1H-benzo[d][1,2,3]triazol-1-yl)-1-oxopropan-2-yl tert-butylcarbonate (1.51 g, 5.20 mmol) in tetrahydrofuran (13 mL) followed by4-dimethylaminopyridine (617 mg, 5.05 mmol). After 5 min, the ice bathwas removed, and the mixture was stirred at ambient temperature for 48h. After this time, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate (50 mL) and washedwith aqueous 10% citric acid (2×25 mL), water (25 mL), and brine (25mL). The organic layer was extracted with saturated aqueous sodiumbicarbonate (2×25 mL). The combined aqueous bicarbonate layers wereacidified to pH ˜3 with 6 N hydrochloric acid and extracted with ethylacetate (4×25 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (silica gel, 0-10% methanol/methylenechloride) to provide(S)-4-(tert-butoxy)-3-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)-4-oxobutanoicacid (507 mg, 28%) as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 12.79(br s, 1H), 5.20 (dd, J=7.2, 4.8 Hz, 1H), 4.95 (q, J=7.2 Hz, 1H),2.86-2.70 (m, 2H), 1.46-1.39 (m, 21H).

Preparation of (S)-1-tert-Butyl 4-(2,5-dioxopyrrolidin-1-yl)2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)succinate

A solution of(S)-4-(tert-butoxy)-3-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)-4-oxobutanoicacid (620 mg, 1.71 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (213 mg, 1.85 mmol) andN,N′-dicyclohexylcarbodiimide (385 mg, 1.87 mmol) and stirred under anitrogen atmosphere for 6.5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide (S)-1-tert-butyl4-(2,5-dioxopyrrolidin-1-yl)2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)succinate (813 mg,quantitative) as a white semi-solid: ¹H NMR (300 MHz, DMSO-d₆) δ5.40-5.29 (m, 1H), 4.98 (q, J=7.2 Hz, 1H), 3.36-3.32 (m, 2H, partiallyobscured by solvent peak), 2.82 (br s, 4H), 1.43-1.40 (m, 21H).

Preparation of (S)-1-tert-Butyl4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)succinate

A suspension of oxycodone (253 mg, 0.802 mmol) in tetrahydrofuran (4 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (0.9 mL, 0.9 mmol).After stirring at 0° C. for 45 min, the ice bath was replaced with a dryice/acetonitrile bath (−45° C.). The mixture was treated dropwise with asolution of (S)-1-tert-butyl 4-(2,5-dioxopyrrolidin-1-yl)2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)succinate (401 mg,0.873 mmol) in tetrahydrofuran (4 mL) and stirred for 30 min. After thistime, the dry ice/acetonitrile bath was replaced with a wet ice bath,and the reaction mixture was treated with chilled saturated aqueousammonium chloride (25 mL) and extracted with ethyl acetate (2×25 mL).The combined organics were washed with water (25 mL) and brine (25 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by reversed phase columnchromatography (50 g C18 column, 20-100% acetonitrile/water) and freezedried to provide (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)succinate (63 mg, 12%)as a fluffy white solid: ESI MS m/z 660 [C₃₄H₄₅NO₁₂+H]⁺.

Preparation of(S)-4-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-(((S)-2-hydroxypropanoyl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt and (S)-1-tert-Butyl4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-(((S)-2-hydroxypropanoyl)oxy)succinate trifluoroacetic acid salt

A solution of (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)succinate (61 mg,0.092 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (0.5 mL) and stirred under a nitrogen atmosphere atambient temperature for 2 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 10-70%acetonitrile/water with 0.1% trifluoroacetic acid) to provide twocompounds. Each compound was freeze dried toafford(S)-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-(((S)-2-hydroxypropanoyl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (20 mg, 35%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 13.42 (br s, 1H), 9.18 (br s, 1H), 6.86 (d,J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.29 (s, 1H), 5.56-5.55 (m, 1H),5.46 (br s, 1H), 5.31 (dd, J=8.1, 4.2 Hz, 1H), 4.99 (s, 1H), 4.21 (q,J=6.9 Hz, 1H), 3.75 (s, 3H), 3.64 (d, J=6.3 Hz, 1H), 3.48-3.40 (m, 1H,partially obscured by water peak), 3.15-2.96 (m, 4H), 2.84 (apparent d,J=4.2 Hz, 3H), 2.66-2.58 (m, 1H), 2.49-2.42 (m, 1H, partially obscuredby solvent peak), 2.32-2.24 (m, 1H), 2.07 (apparent d, J=18.0 Hz, 1H),1.64 (d, J=11.7 Hz, 1H), 1.31 (d, J=6.9 Hz, 3H); ESI MS m/z 504[C₂₅H₂₉NO₁₀+H]⁺; HPLC (Method A) 95.0% (AUC), t_(R)=7.36 min; and(S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-(((S)-2-hydroxypropanoyl)oxy)succinate trifluoroacetic acid salt (10mg, 15%) as a fluffy white solid: ¹H NMR (300 MHz, CDCl₃) δ 9.18 (br s,1H), 6.86 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.27 (s, 1H),5.56-5.54 (m, 1H), 5.48 (br s, 1H), 5.24 (dd, J=7.5, 4.8 Hz, 1H), 4.99(s, 1H), 4.21 (q, J=6.6 Hz, 1H), 3.74 (s, 3H), 3.64 (d, J=6.0 Hz, 1H),3.46-3.40 (m, 1H, partially obscured by water peak), 3.15-2.97 (m, 4H),2.85 (apparent d, J=4.8 Hz, 3H), 2.66-2.57 (m, 1H), 2.49-2.42 (m, 1H,partially obscured by solvent peak), 2.33-2.24 (m, 1H), 2.07 (apparentd, J=18.3 Hz, 1H), 1.64 (d, J=12.0 Hz, 1H), 1.41 (s, 9H), 1.32 (d, J=6.9Hz, 3H); ESI MS m/z 560 [C₂₉H₃₇NO₁₀+H]⁺; HPLC (Method A) 97.7% (AUC),t_(R)=9.28 min.

Preparation of (R)-2,5-Dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate

A solution of (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid(696 mg, 4.00 mmol) in tetrahydrofuran (40 mL) was treated withN-hydroxysuccinimide (506 mg, 4.40 mmol) andN,N′-dicyclohexylcarbodiimide (906 mg, 4.40 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (R)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (1.40 g, quantitative)as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 4.77 (dd, J=6.3, 3.6 Hz,1H), 3.28 (dd, J=17.4, 3.9 Hz, 1H), 3.10 (dd, J=17.1, 6.3 Hz, 1H), 2.85(s, 4H), 1.63 (s, 3H), 1.58 (s, 3H).

Preparation of(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate

A suspension of oxycodone (500 mg, 1.59 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.8 mL, 1.8 mmol).After addition was complete, the mixture was stirred at −50° C. for 45min. The mixture was treated dropwise with a solution of(R)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (640 mg, 2.40 mmol) intetrahydrofuran (8 mL). After addition was complete, the mixture wasstirred at −50° C. for 30 min. After this time, the reaction mixture wastreated with saturated aqueous ammonium chloride (15 mL) and extractedwith ethyl acetate (3×15 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (50 gC18 column, 10-100% acetonitrile/water) and freeze dried to provide(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (43 mg, 6%) as awhite solid: ESI MS m/z 472 [C₂₅H₂₉NO₈+H]⁺.

Preparation of(R)-2-Hydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (43 mg, 0.090 mmol)was treated with 1 M hydrogen chloride solution in 1,4-dioxanes (1 mL)and water (a few drops) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. This material was purified byreversed phase column chromatography (50 g C18 column, 5-40%acetonitrile/water) and freeze dried to provide(R)-2-hydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacidtrifluoroacetic acid salt (28 mg, 71%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 12.7 (s, 1H), 9.19 (s, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.75(d, J=8.4 Hz, 1H), 6.28 (s, 1H), 5.63 (s, 1H), 5.53-5.51 (m, 1H), 4.98(s, 1H), 4.34 (dd, J=7.8, 2.1 Hz, 1H), 3.76 (s, 3H), 3.64 (d, J=6.3 Hz,1H), 3.43 (d, J=20.1 Hz, 1H), 3.15-3.07 (m, 2H), 2.89-2.82 (m, 4H),2.72-2.61 (m, 2H), 2.46-2.42 (m, 1H), 2.33-2.26 (m, 1H), 2.05 (d, J=18.0Hz, 1H), 1.64 (d, J=11.5 Hz, 1H); ESI MS m/z 432 [C₂₂H₂₅NO₈+H]⁺, HPLC(Method A) 97.2% (AUC), t_(R)=7.04 min.

Preparation of(S)-2-(((S)-5-(tert-Butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoicacid

(S)-Lactic acid (270 mg, 3.00 mmol), (S)-1-tert-butyl5-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)amino)pentanedioate(1.00 g, 2.50 mmol), 4-(dimethylamino)pyridine (31 mg, 0.250 mmol), andpyridine (237 mg, 3.00 mmol) were combined and heated at 60° C. under anitrogen atmosphere for 48 h. After this time, the solvent was removedunder reduced pressure, and the residue was participated between ethylacetate (20 mL) and 10% aqueous citric acid. The organic layer wasseparated and extracted with saturated aqueous sodium bicarbonate (20ml). The aqueous phase was collected and acidified to pH=3 with 6 Nhydrochloric acid, and the mixture was extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(S)-2-(((S)-5-(tert-butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoicacid (726 mg, 77%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ5.19-5.12 (m, 2H), 2.51-2.42 (m, 2H), 2.18 (m, 1H), 1.91 (m, 1H), 1.54(d, J=7.2 Hz, 3H), 1.47 (s, 9H), 1.45 (s, 9H), CO₂H and NH protons notobserved.

Preparation of (S)-1-tert-Butyl5-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate

A solution of(S)-2-(((S)-5-(tert-butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoicacid (726 mg, 1.93 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (245 mg, 2.13 mmol) andN,N′-dicyclohexylcarbodiimide (439 mg, 2.13 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-1-tert-butyl5-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (1.03 g, quantitative) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 5.42 (dd, J=14.1, 7.2 Hz, 1H),5.08 (m, 1H), 2.84 (s, 4H), 2.53-2.46 (m, 2H), 2.20 (m, 1H), 1.91 (m,1H), 1.67 (d, J=7.2 Hz, 3H), 1.47 (s, 9H), 1.45 (s, 9H), NH proton notobserved.

Preparation of (S)-1-tert-Butyl5-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate

A suspension of oxycodone (400 mg, 1.27 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.4 mL, 1.4 mmol).After addition was complete, the mixture was stirred at −50° C. for 45min. The mixture was treated dropwise with a solution of(S)-1-tert-butyl5-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (640 mg, 1.40 mmol) intetrahydrofuran (8 mL). After addition was complete, the mixture wasstirred at −50° C. for 30 min. After this time, the reaction mixture wastreated with saturated aqueous ammonium chloride (15 mL) and extractedwith ethyl acetate (3×15 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (50 gC18 column, 10-100% acetonitrile/water) and freeze dried to provide(S)-1-tert-butyl5-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (240 mg, 28%) as a whitesolid: ESI MS m/z 673 [C₃₅H₄₈N₂O₁₁+H]⁺.

Preparation of(S)-2-Amino-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid bis(trifluoroacetic acid salt)

A solution of (S)-1-tert-butyl5-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (0.18 g, 0.27 mmol) inmethylene chloride (1 mL) was treated with trifluoroacetic acid (1 mL)and stirred under a nitrogen atmosphere at ambient temperature for 1 h.After this time, the reaction mixture was concentrated under reducedpressure. This material was purified by reversed phase columnchromatography (50 g C18 column, 5-40% acetonitrile/water) and freezedried to provide(S)-2-amino-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid bis(trifluoroacetic acid salt) (100 mg, 72%) as a white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.29 (s, 3H), 6.86 (d, J=8.4 Hz,1H), 6.76 (d, J=8.1 Hz, 1H), 6.34 (s, 1H), 5.60-5.58 (m, 1H), 5.14 (dd,J=13.8, 7.2 Hz, 1H), 5.00 (s, 1H), 3.76 (s, 3H), 3.66 (d, J=6.3 Hz, 1H),3.43 (d, J=20.1 Hz, 1H), 3.16-3.07 (m, 2H), 2.85 (s, 3H), 2.72-2.61 (m,3H), 2.46-2.42 (m, 1H), 2.33-2.26 (m, 1H), 2.15-1.99 (m, 3H), 2.07 (d,J=18.0 Hz, 1H), 1.64 (d, J=11.5 Hz, 1H), 1.51 (d, J=7.2 Hz, 3H), CO₂Hproton not observed; ESI MS m/z 517 [C₂₆H₃₂N₂O₉+H], HPLC (Method A)97.8% (AUC), t_(R)=7.13 min.

Preparation of(S)-2-((S)-3-Acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid

A solution of (S)-1-tert-butyl 4-(2,5-dioxopyrrolidin-1-yl)2-acetoxysuccinate (1.66 g, 5.05 mmol), (S)-mandelic acid (861 mg, 5.66mmol), and 4-dimethylaminopyridine (68 mg, 0.56 mmol) in tetrahydrofuran(30 mL) was treated with pyridine (0.82 mL, 10 mmol) and heated at 50°C. under a nitrogen atmosphere for 64 h. After this time, the reactionmixture was cooled to room temperature and concentrated under reducedpressure. The residue was dissolved in ethyl acetate (50 mL); washedwith aqueous 10% citric acid (2×25 mL), water (25 mL), and brine (25mL); dried over sodium sulfate; filtered; and concentrated under reducedpressure. The crude residue was purified by column chromatography(silica gel, 0-10% methanol/methylene chloride) to provide(S)-2-(((S)-3-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid (849 mg, 46%) as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 13.31(s, 1H), 7.47-7.40 (m, 5H), 5.88 (s, 1H), 5.23 (dd, J=8.7, 4.2 Hz, 1H),3.05 (dd, J=16.8, 4.2 Hz, 1H), 2.94 (dd, J=16.8, 8.7 Hz, 1H), 2.05 (s,3H), 1.38 (s, 9H); ESI MS m/z 731 [(2×C₁₈H₂₂O₈)−H]⁻.

Preparation of (S)-1-tert-Butyl4-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate

A solution of(S)-2-(((S)-3-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid (845 mg, 2.31 mmol) in tetrahydrofuran (23 mL) was treated withN-hydroxysuccinimide (292 mg, 2.54 mmol) andN,N′-dicyclohexylcarbodiimide (541 mg, 2.62 mmol) and stirred under anitrogen atmosphere for 16 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide (S)-1-tert-butyl4-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate (1.20 g, quantitative) as a white semi-solid: ¹H NMR(300 MHz, DMSO-d₆) δ 7.59-7.56 (m, 2H), 7.50-7.47 (m, 3H), 6.57 (s, 1H),5.22 (dd, J=8.1, 4.5 Hz, 1H), 3.10 (dd, J=16.8, 4.5 Hz, 1H), 3.00 (dd,J=16.8, 8.4 Hz, 1H), 2.78 (br s, 4H), 2.04 (s, 3H), 1.37 (s, 9H).

Preparation of (S)-1-tert-Butyl4-((S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate

A suspension of oxycodone (335 mg, 1.06 mmol) in tetrahydrofuran (5 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (1.2 mL, 1.2 mmol). Afterstirring at 0° C. for 1 h, the ice bath was replaced with a dryice/acetonitrile bath (−45° C.). The mixture was treated dropwise with asolution of (S)-1-tert-butyl4-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate (533 mg, 1.15 mmol) in tetrahydrofuran (5 mL). Thedry ice was removed from the acetonitrile bath, and the bath temperatureincreased to −10° C. over 30 min. After this time, the reaction mixturewas treated with saturated aqueous ammonium chloride (25 mL) andextracted with ethyl acetate (2×25 mL). The combined organics werewashed with brine (25 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified byreversed phase column chromatography (50 g C18 column, 10-100%acetonitrile/water) and freeze dried to provide (S)-1-tert-butyl4-((S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate (71 mg, 10%) as a fluffy white solid: ESI MS m/z 664[C₃₆H₄₁NO₁₁+H]⁺.

Preparation of(S)-2-Acetoxy-4-((S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of (S)-1-tert-butyl4-((S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate (70 mg, 0.11 mmol) in methylene chloride (2 mL) wastreated with trifluoroacetic acid (0.5 mL) and stirred under a nitrogenatmosphere at ambient temperature for 3 h. After this time, the reactionmixture was concentrated under reduced pressure. The residue waspurified by reversed phase column chromatography (50 g C18 column,10-80% acetonitrile/water with 0.1% trifluoroacetic acid) and freezedried to provide(S)-2-acetoxy-4-((S)-2-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid trifluoroacetic acid salt (25 mg, 33%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 13.40 (br s, 1H), 9.16 (br s, 1H), 7.57-7.54(m, 2H), 7.48-7.46 (m, 3H), 6.81 (d, J=8.4 Hz, 1H), 6.73 (d, J=8.4 Hz,1H), 6.29 (s, 1H), 6.17 (s, 1H), 5.55 (dd, J=6.0, 2.1 Hz, 1H), 5.33 (dd,J=8.7, 3.9 Hz, 1H), 4.95 (s, 1H), 3.75 (br s, 4H), 3.44-3.38 (m, 1H,partially obscured by water peak), 3.14-2.97 (m, 4H), 2.83 (apparent d,J=4.2 Hz, 3H), 2.68-2.57 (m, 1H), 2.49-2.40 (m, 1H, partially obscuredby solvent peak), 2.31-2.22 (m, 1H), 2.09-2.04 (m, 1H), 2.04 (s, 3H),1.63 (d, J=12.0 Hz, 3H); ESI MS m/z 608 [C₃₂H₃₃NO₁₁+H]⁺; HPLC (Method A)98.0% (AUC), t_(R)=9.62 min.

Preparation of(2R,3R)-2,3-Diacetoxy-4-(((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid

(S)-Di-tert-butyl 2-hydroxysuccinate (968 mg, 3.93 mmol),(3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate (1.06 g, 4.91 mmol),pyridine (279 mg, 3.54 mmol), and N,N-dimethylformamide (2 mL) werecombined and stirred at 0° C. under a nitrogen atmosphere for 2 h. Afterthis time, saturated sodium bicarbonate (15 mL) was added, and theresulting aqueous solution was washed with ethyl acetate (10 mL). Theaqueous phase was collected and acidified to pH=3 with 6 N hydrochloricacid, and the mixture was extracted with ethyl acetate (2×20 mL). Thecombined organics were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(2R,3R)-2,3-diacetoxy-4-(((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid (1.74 g, 95%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.80 (d,J=3.0 Hz, 1H), 5.68 (d, J=3.0 Hz, 1H), 5.30 (dd, J=7.2, 5.1 Hz, 1H),2.77-2.74 (m, 2H), 2.20 (s, 3H), 2.18 (s, 3H), 1.46 (s, 9H), 1.44 (s,9H), CO₂H proton not observed.

Preparation of (2R,3R)-1-((S)-1,4-Di-tert-butoxy-1,4-dioxobutan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate

A solution of(2R,3R)-2,3-diacetoxy-4-(((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid (1.74 g, 3.76 mmol) in tetrahydrofuran (25 mL) was treated withN-hydroxysuccinimide (476 mg, 4.14 mmol) andN,N′-dicyclohexylcarbodiimide (929 mg, 4.51 mmol) and stirred under anitrogen atmosphere for 4 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide(2R,3R)-1-((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (2.06 g) as a yellowsolid: ¹H NMR (300 MHz, CDCl₃) δ 6.04 (d, J=3.0 Hz, 1H), 5.95 (d, J=2.7Hz, 1H), 5.32 (dd, J=8.1, 4.2 Hz, 1H), 2.85-2.74 (m, 6H), 2.25 (s, 3H),2.23 (s, 3H), 1.46 (s, 9H), 1.44 (s, 9H).

Preparation of (2R,3R)-1-((S)-1,4-di-tert-Dutoxy-1,4-dioxobutan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate

A suspension of oxycodone (380 mg, 1.22 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.3 mL, 1.3 mmol).After addition was complete, the mixture was stirred at −50° C. for 45min. The mixture was treated dropwise with a solution of(2R,3R)-1-((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (750 mg, 1.30 mmol)in tetrahydrofuran (8 mL). After addition was complete, the mixture wasstirred at −50° C. for 30 min. After this time, the reaction mixture wastreated with saturated aqueous ammonium chloride (15 mL) and extractedwith ethyl acetate (3×15 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (50 gC18 column, 10-100% acetonitrile/water) and freeze dried to provide(2R,3R)-1-((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (120 mg, 11%) as a white solid: ESI MS m/z 760[C₃₈H₄₉NO₁₅+H]⁺.

Preparation of(S)-2-(((2R,3R)-2,3-Diacetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid trifluoroacetic acid salt

A solution of (2R,3R)-1-((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (0.12 g, 0.16 mmol) in methylene chloride (1 mL)was treated with trifluoroacetic acid (1 mL) and stirred under anitrogen atmosphere at ambient temperature for 1 h. After this time, thereaction mixture was concentrated under reduced pressure. This materialwas purified by reversed phase column chromatography (50 g C18 column,5-40% acetonitrile/water) and freeze dried to provide(S)-2-(((2R,3R)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacidtrifluoroacetic acid salt (66 mg, 65%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 13.5 (s, 1H), 12.6 (s, 1H), 9.18 (s, 1H), 6.88 (d, J=8.1Hz, 1H), 6.77 (d, J=8.1 Hz, 1H), 6.34 (s, 1H), 5.85 (d, J=2.7 Hz, 1H),5.78 (d, J=2.7 Hz, 1H), 5.55 (dd, J=6.0, 2.1 Hz, 1H), 5.30 (dd, J=8.4,3.6 Hz, 1H), 4.88 (s, 1H), 3.75 (s, 3H), 3.65 (d, J=6.0 Hz, 1H), 3.43(d, J=20.1 Hz, 1H), 3.16-3.07 (m, 2H), 2.90-2.80 (m, 5H), 2.64-2.61 (m,1H), 2.41-2.32 (m, 1H), 2.32-2.27 (m, 1H), 2.20 (s, 3H), 2.12 (s, 3H),2.08 (d, J=18.3 Hz, 1H), 1.64 (d, J=11.7 Hz, 1H); ESI MS m/z 648[C₃₀H₃₃NO₁₅+H]⁺, HPLC (Method A) 96.7% (AUC), t_(R)=8.23 min.

Preparation of(S)-5-(2-(1H-Benzo[d][1,2,3]triazol-1-yl)-2-oxoethyl)-2,2-dimethyl-1,3-dioxolan-4-one

A solution of (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid(1.51 g, 8.66 mmol) in tetrahydrofuran (40 mL) was treated withbenzotriazole (1.14 g, 9.60 mmol) and N,N′-dicyclohexylcarbodiimide(2.00 g, 9.69 mmol) and stirred under a nitrogen atmosphere for 16 h.After this time, the reaction mixture was filtered to remove the soliddicyclohexylurea byproduct. The solid was washed with diethyl ether, andthe combined filtrate and washings were concentrated under reducedpressure to provide(S)-5-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-oxoethyl)-2,2-dimethyl-1,3-dioxolan-4-one(2.99 g, quantitative) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ8.30-8.23 (m, 2H), 7.84-7.79 (m, 1H), 7.67-7.61 (m, 1H), 5.19 (dd,J=6.0, 3.9 Hz, 1H), 4.17 (dd, J=18.0, 3.9 Hz, 1H), 3.91 (dd, J=18.0, 6.0Hz, 1H), 1.59 (s, 6H).

Preparation of(S)-4-(tert-Butoxy)-3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-4-oxobutanoicacid

A solution of (S)-4-(tert-butoxy)-3-hydroxy-4-oxobutanoic acid (1.46 g,7.69 mmol) in tetrahydrofuran (15 mL) was cooled in an ice bath under anitrogen atmosphere and treated with a solution of(S)-5-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-oxoethyl)-2,2-dimethyl-1,3-dioxolan-4-one(2.38 g, 8.66 mmol) in tetrahydrofuran (15 mL) followed by4-dimethylaminopyridine (953 mg, 7.80 mmol). After 10 min, the ice bathwas removed, and the mixture was stirred at ambient temperature for 48h. After this time, the reaction mixture was diluted with ethyl acetate(100 mL), washed with aqueous 10% citric acid (50 mL) and brine (25 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by column chromatography(silica gel, 0-10% methanol/methylene chloride) to provide(S)-4-(tert-butoxy)-3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-4-oxobutanoicacid (1.09 g, 41%) as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 12.62(s, 1H), 5.14 (dd, J=7.8, 4.8 Hz, 1H), 4.85 (overlapping dd, J=4.5, 4.5Hz, 1H), 2.84-2.67 (m, 4H), 1.53 (s, 6H), 1.40 (s, 9H).

Preparation of (S)-1-tert-Butyl 4-(2,5-dioxopyrrolidin-1-yl)2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)succinate

A solution of(S)-4-(tert-butoxy)-3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-4-oxobutanoicacid (1.04 g, 3.01 mmol) in tetrahydrofuran (30 mL) was treated withN-hydroxysuccinimide (383 mg, 3.33 mmol) andN,N′-dicyclohexylcarbodiimide (687 mg, 3.33 mmol) and stirred under anitrogen atmosphere for 16 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide (S)-1-tert-butyl4-(2,5-dioxopyrrolidin-1-yl)2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)succinate (1.46g, quantitative) as a white semi-solid. The material used withoutfurther purification.

Preparation of (S)-1-tert-Butyl4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)succinate

A suspension of oxycodone (493 mg, 1.56 mmol) in tetrahydrofuran (7 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.8 mL, 1.8 mmol).After stirring at 0° C. for 30 min, the ice bath was replaced with a dryice/acetonitrile bath (−45° C.). The mixture was treated dropwise with asolution of (S)-1-tert-butyl 4-(2,5-dioxopyrrolidin-1-yl)2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)succinate (745mg, 1.68 mmol) in tetrahydrofuran (8 mL). The dry ice was removed fromthe acetonitrile bath, and the bath temperature increased to −10° C.over 30 min. After this time, the reaction mixture was treated withchilled saturated aqueous ammonium chloride (25 mL) and extracted withethyl acetate (2×25 mL). The combined organics were washed with brine(25 mL), dried over sodium sulfate, filtered, and concentrated underreduced pressure. The crude residue was purified by reversed phasecolumn chromatography (150 g C18 column, 10-100% acetonitrile/water) andfreeze dried to provide (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)succinate (146mg, 15%) as a fluffy white solid: ESI MS m/z 644 [C₃₃H₄₁NO₁₂+H]⁺.

Preparation of(S)-4-((S)-1-Carboxy-3-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropoxy)-2-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt

A solution of (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)succinate (145mg, 0.225 mmol) in 1,4-dioxane (4 mL) was treated with a 4.0 M solutionof hydrogen chloride in 1,4-dioxane (0.4 mL) followed by water (4 drops)and stirred under a nitrogen atmosphere at ambient temperature for 2 h.Additional hydrogen chloride solution (0.4 mL) was added, and themixture was stirred for 1 h. After this time, the reaction mixture waspartially concentrated under reduced pressure, diluted with acetonitrileand water, and freeze-dried. The residue was suspended in methylenechloride (3 mL) was treated with trifluoroacetic acid (1 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 2 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 10-30% acetonitrile/water with 0.1% trifluoroacetic acid) andfreeze dried to provide(S)-4-((S)-1-carboxy-3-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropoxy)-2-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt (88 mg, 59%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 13.41 (br s, 1H), 12.69 (br s, 1H), 9.19 (br s,1H), 6.86 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.31 (br s, 1H),5.57 (dd, J=5.7, 1.5 Hz, 1H), 5.55 (br s, 1H), 5.30 (dd, J=7.8, 4.5 Hz,1H), 4.99 (s, 1H), 4.32 (dd, J=7.8, 4.2 Hz, 1H), 3.75 (s, 3H), 3.65 (d,J=6.3 Hz, 1H), 3.43 (d, J=20.1 Hz, 1H), 3.16-2.95 (m, 4H), 2.84 (s, 3H),2.81-2.58 (m, 3H), 2.49-2.43 (m, 1H, partially obscured by solventpeak), 2.32-2.24 (m, 1H), 2.07 (apparent d, J=18.0 Hz, 1H), 1.64 (d,J=11.1 Hz, 1H); ESI MS m/z 548 [C₂₆H₂₉NO₁₂+H]⁺; HPLC (Method A) 92.0%(AUC), t_(R)=7.23 min.

Preparation of (S)-tert-Butyl2-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)carbamoyl)pyrrolidine-1-carboxylate

A suspension(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate bis(2,2,2-trifluoroacetate) (125 mg,0.182 mmol) and (S)-1-tert-butyl 2-(2,5-dioxopyrrolidin-1-yl)pyrrolidine-1,2-dicarboxylate (86 mg, 0.275 mmol) in methylene chloride(3 mL) was treated with N,N-diisopropylethylamine (0.13 mL, 0.75 mmol)and stirred under a nitrogen atmosphere for 30 min. After this time, thereaction mixture was diluted with methylene chloride (15 mL) and washedwith saturated aqueous ammonium chloride (10 mL). The organic layer wasdried over sodium sulfate, filtered, and concentrated under reducedpressure to provide (S)-tert-butyl2-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)carbamoyl)pyrrolidine-1-carboxylate(127 mg, quantitative) as a colorless semi-solid: ESI MS m/z 656[C₃₄H₄₅N₃O₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-pyrrolidine-2-carboxamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt)

A solution of (S)-tert-butyl2-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)carbamoyl)pyrrolidine-1-carboxylate(119 mg, 0.182 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 30 min. After this time, the reaction mixturewas concentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 5-70%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-pyrrolidine-2-carboxamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt) (67 mg, 47%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 9.20 (br s, 2H), 8.61 (t, J=5.7 Hz, 1H), 8.54 (brs, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.1 Hz, 1H), 6.31 (br s, 1H),5.59 (dd, J=6.0, 2.1 Hz, 1H), 5.12 (q, J=7.2 Hz, 1H), 5.00 (s, 1H),4.13-4.09 (m, 1H), 3.76 (s, 3H), 3.66 (d, J=6.0 Hz, 1H), 3.51-3.29 (m,4H), 3.22-3.07 (m, 4H), 2.85 (apparent d, J=4.5 Hz, 3H), 2.70-2.58 (m,2H), 2.49-2.41 (m, 1H, partially obscured by solvent peak), 2.34-2.19(m, 2H), 2.06 (apparent d, J=18.0 Hz, 1H), 1.92-1.77 (m, 3H), 1.64 (d,J=11.1 Hz, 1H), 1.51 (d, J=6.9 Hz, 3H); ESI MS m/z 556 [C₂₉H₃₇N₃O₈+H]⁺;HPLC (Method A) 97.4% (AUC), t_(R)=7.32 min.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-acetamido-6-((tert-butoxycarbonyl)amino)hexanoate

A solution of (S)-2-acetamido-6-((tert-butoxycarbonyl)amino)hexanoicacid (1.00 g, 3.47 mmol) in tetrahydrofuran (20 mL) was treated withN-hydroxysuccinimide (439 mg, 3.81 mmol) andN,N′-dicyclohexylcarbodiimide (785 mg, 3.81 mmol) and stirred under anitrogen atmosphere for 2 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-2,5-dioxopyrrolidin-1-yl2-acetamido-6-((tert-butoxycarbonyl)amino)hexanoate (1.49 mg) as a whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 6.27 (m, 1H), 4.94 (m, 1H), 4.69 (m,1H), 3.15-3.13 (m, 2H), 2.87 (s, 4H), 2.08 (s, 3H), 2.02-1.83 (m, 2H),1.55-1.22 (m, 4H), 1.45 (s, 9H).

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-acetamido-6-((tert-butoxycarbonyl)amino)hexanamido)propanoyl)oxy)propanoate

A suspension(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate bis(2,2,2-trifluoroacetate) (166 mg,0.242 mmol) and (S)-2,5-dioxopyrrolidin-1-yl2-acetamido-6-((tert-butoxycarbonyl)amino)hexanoate (141 mg, 0.366 mmol)in methylene chloride (3 mL) was treated with N,N-diisopropylethylamine(0.17 mL, 0.98 mmol) and stirred under a nitrogen atmosphere for 30 min.After this time, the reaction mixture was diluted with methylenechloride (15 mL) and washed with saturated aqueous ammonium chloride (10mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-acetamido-6-((tert-butoxycarbonyl)amino)hexanamido)propanoyl)oxy)propanoate(181 mg, quantitative) as a colorless semi-solid: ESI MS m/z 729[C₃₇H₅₂N₄O₁₁+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-acetamido-6-aminohexanamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt)

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-acetamido-6-((tert-butoxycarbonyl)amino)hexanamido)propanoyl)oxy)propanoate(176 mg, 0.242 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 30 min. After this time, the reaction mixturewas concentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 5-70%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-acetamido-6-aminohexanamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt)(94 mg, 44%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 9.19 (br s, 1H), 8.05-7.98 (m, 2H), 7.65 (br s, 3H),6.86 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.32 (s, 1H), 5.59 (dd,J=5.7, 1.8 Hz, 1H), 5.10 (q, J=6.9 Hz, 1H), 5.00 (s, 1H), 4.19-4.12 (m,1H), 3.75 (s, 3H), 3.66 (d, J=6.0 Hz, 1H), 3.43 (d, J=19.8 Hz, 1H),3.35-3.25 (m, 2H), 3.16-3.07 (m, 2H), 2.85 (apparent d, J=4.5 Hz, 3H),2.79-2.70 (m, 2H), 2.65-2.53 (m, 3H, partially obscured by solventpeak), 2.49-2.43 (m, 1H, partially obscured by solvent peak), 2.34-2.26(m, 1H), 2.06 (apparent d, J=18.3 Hz, 1H), 1.84 (s, 3H), 1.67-1.40 (m,8H), 1.33-1.20 (m, 2H); ESI MS m/z 629 [C₃₂H₄₄N₄O₉+H]⁺; HPLC (MethodA) >99% (AUC), t_(R)=7.16 min.

Preparation of(S)-2-((4-(tert-Butoxy)-4-oxobutanoyl)oxy)-4-ethoxy-4-oxobutanoic acid

A mixture of (S)-4-ethoxy-2-hydroxy-4-oxobutanoic acid (1.51 g, 9.32mmol), tert-butyl (2,5-dioxopyrrolidin-1-yl) succinate (2.65 g, 9.78mmol), pyridine (1.0 mL, 12 mmol), and 4-dimethylaminopyridine (150 mg,1.23 mmol) in tetrahydrofuran (40 mL) was stirred at reflux for 24 h.After this time, the mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate, washed with 10% citric acid, and extracted with saturatedsodium bicarbonate. The aqueous layer was collected, carefully treatedwith 6N hydrochloric acid until acidic by pH paper analysis, and thenextracted with ethyl acetate. The organic extracts were dried oversodium sulfate, filtered, and concentrated to provide(S)-2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)-4-ethoxy-4-oxobutanoic acid(1.47 g, 49%): ¹H NMR (300 MHz, CDCl₃) δ 5.56 (t, J=6.0 Hz, 1H), 4.19(q, J=7.1 Hz, 2H), 2.93 (d, J=6.0 Hz, 2H), 2.71-2.52 (m, 4H), 1.44 (s,9H), 1.27 (t, J=7.1 Hz, 3H), CO₂H proton not observed.

Preparation of (S)-1-(2,5-Dioxopyrrolidin-1-yl) 4-ethyl2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate

A mixture of(S)-2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)-4-ethoxy-4-oxobutanoic acid(1.40 g, 4.40 mmol) and N-hydroxysuccinimide (560 mg, 4.87 mmol) intetrahydrofuran (25 mL) was treated with N,N′-dicyclohexylcarbodiimide(1.00 g, 4.85 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (20 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide (S)-1-(2,5-dioxopyrrolidin-1-yl) 4-ethyl2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate (1.9 g) that was usedwithout purification: ¹H NMR (300 MHz, CDCl₃) δ 5.82 (dd, J=7.1, 5.2 Hz,1H), 4.22 (dd, J=7.1 Hz, 2H), 3.05-3.03 (m, 2H), 2.84 (s, 4H), 2.72-2.65(m, 2H), 2.60-2.53 (m, 2H), 1.44 (s, 9H), 2.28 (t, J=7.1 Hz, 3H).

Preparation of (S)-4-Ethyl1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate

A suspension of oxycodone (984 mg, 3.12 mmol) in tetrahydrofuran (15 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (3.7 mL, 3.7 mmol).After stirring at 0° C. for 30 min, the ice bath was replaced with a dryice/acetonitrile bath (−45° C.). The mixture was treated dropwise with asolution of (S)-1-(2,5-dioxopyrrolidin-1-yl) 4-ethyl2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate (1.55 g, 3.74 mmol) intetrahydrofuran (15 mL). The dry ice was removed from the acetonitrilebath, and the bath temperature increased to −10° C. over 30 min. Afterthis time, the reaction mixture was treated with chilled saturatedaqueous ammonium chloride (50 mL) and extracted with ethyl acetate (2×50mL). The combined organics were washed with brine (50 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (150g C18 column, 10-100% acetonitrile/water) and freeze dried to provide(S)-4-ethyl1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate (177 mg, 9%) as a whitesolid: ESI MS m/z 616 [C₃₂H₄₁NO₁₁+H]⁺.

Preparation of4-(((S)-4-Ethoxy-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of (S)-4-ethyl1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate (175 mg, 0.284 mmol) inmethylene chloride (3 mL) was treated with trifluoroacetic acid (1 mL)and stirred under a nitrogen atmosphere at ambient temperature for 4 h.After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 10-80% acetonitrile/water with 0.1%trifluoroacetic acid) and freeze dried to provide4-(((S)-4-ethoxy-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (124 mg, 65%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 12.28 (br s, 1H), 9.19 (br s, 1H), 6.85 (d, J=8.4Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.31 (s, 1H), 5.61 (dd, J=5.7, 1.8 Hz,1H), 5.47 (t, J=5.4 Hz, 1H), 4.96 (s, 1H), 4.13 (q, J=6.9 Hz, 2H), 3.74(s, 3H), 3.65 (d, J=6.0 Hz, 1H), 3.43 (d, J=19.8 Hz, 1H), 3.16-3.07 (m,2H), 2.98 (d, J=6.6 Hz, 2H), 2.84 (apparent d, J=4.8 Hz, 3H), 2.69-2.58(m, 3H), 2.49-2.43 (m, 1H, partially obscured by solvent peak),2.34-2.26 (m, 1H), 2.07 (apparent d, J=18.3 Hz, 1H), 1.65 (d, J=10.8 Hz,1H), 1.21 (t, J=6.9 Hz, 3H), two protons obscured by the solvent peaks;ESI MS m/z 560 [C₂₈H₃₃NO₁₁+H]⁺; HPLC (Method A) >99% (AUC), t_(R)=8.78min.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)propanoyl)oxy)propanoate

A suspension(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate bis(2,2,2-trifluoroacetate) (104 mg,0.152 mmol) and (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)amino)-4-methylpentanoate (75 mg, 0.23 mmol) inmethylene chloride (2 mL) was treated with N,N-diisopropylethylamine(0.11 mL, 0.63 mmol) and stirred under a nitrogen atmosphere for 30 min.After this time, the reaction mixture was diluted with methylenechloride (15 mL) and washed with saturated aqueous ammonium chloride (10mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)propanoyl)oxy)propanoate(100 mg, 98%) as a colorless semi-solid: ESI MS m/z 672[C₃₅H₄₉N₃O₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-amino-4-methylpentanamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt)

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)propanoyl)oxy)propanoate(100 mg, 0.149 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 45 min. After this time, the reaction mixturewas concentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 10-80%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-amino-4-methylpentanamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt) (57 mg, 48%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 9.19 (br s, 1H), 8.63 (t, J=5.4 Hz, 1H), 8.11 (brs, 3H), 6.86 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.32 (br s, 1H),5.59 (dd, J=5.7, 1.8 Hz, 1H), 5.13 (q, J=6.9 Hz, 1H), 5.00 (s, 1H), 3.76(s, 3H), 3.67-3.65 (m, 2H), 3.53-3.40 (m, 2H), 3.35-3.24 (m, 1H),3.16-3.07 (m, 2H), 2.85 (apparent d, J=4.5 Hz, 3H), 2.73-2.59 (m, 3H),2.49-2.43 (m, 1H, partially obscured by solvent peak), 2.34-2.26 (m,1H), 2.06 (apparent d, J=18.3 Hz, 1H), 1.66-1.50 (m, 7H), 0.90-0.87 (m,6H); ESI MS m/z 572 [C₃₀H₄₁N₃O₈+H]⁺; HPLC (Method A) 95.1% (AUC),t_(R)=7.76 min.

Preparation of (2R,3R)-2,3-Diacetoxy-4-methoxy-4-oxobutanoic acid

A mixture of (3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate (5.66g, 26.2 mmol) in methanol (26 mL) was stirred at room temperature for 30min. After this time, the mixture was concentrated to dryness to provide(2R,3R)-2,3-diacetoxy-4-methoxy-4-oxobutanoic acid (6.30 g, 97%): ¹H NMR(300 MHz, DMSO-d₆) δ 5.63 (d, J=2.9 Hz, 1H), 5.52 (d, J=2.9 Hz, 1H),3.70 (s, 3H), 2.12 (s, 3H), 2.10 (s, 3H), CO₂H proton not observed.

Preparation of (2R,3R)-1-tert-Butyl 4-methyl 2,3-diacetoxysuccinate

A mixture of (2R,3R)-2,3-diacetoxy-4-methoxy-4-oxobutanoic acid (6.30 g,25.4 mmol) and tert-butanol (6.5 mL, 68 mmol) in methylene chloride (50mL) at 0° C. was treated with N,N-dicyclohexylcarbodiimide (6.70 g, 32.5mmol). After stirring for 1 h, the ice bath was removed and the reactionmixture was stirred at ambient temperature for 18 h. After this time,the mixture was filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by column chromatography (120g silica gel column, 5-70% ethyl acetate/heptane) to provide(2R,3R)-1-tert-butyl 4-methyl 2,3-diacetoxysuccinate (4.2 g, 54%): ¹HNMR (300 MHz, CDCl₃) δ 5.73 (d, J=2.8 Hz, 1H), 5.60 (d, J=2.8 Hz, 1H),3.78 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H), 1.45 (s, 9H).

Preparation of (2R,3R)-1-tert-Butyl 4-methyl 2,3-dihydroxysuccinate

A solution of (2R,3R)-1-tert-butyl 4-methyl 2,3-diacetoxysuccinate (4.15g, 13.7 mmol) in methanol (28 mL) was treated with sodium methoxide (25%in methanol, 0.30 mL, 1.3 mmol), and the mixture was stirred at roomtemperature for 19 h. After this time, the reaction mixture was treatedwith a few drops of 2N hydrochloric acid, until neutral by pH paperanalysis. The mixture was partially concentrated, and the residue wasdissolved in ethyl acetate, washed with saturated ammonium chloride andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure to provide (2R,3R)-1-tert-butyl 4-methyl2,3-dihydroxysuccinate (2.62 g, 87%): ¹H NMR (300 MHz, CDCl₃) δ 4.51(dd, J=7.5, 1.7 Hz, 1H), 4.41 (d, J=6.3, 1.7 Hz, 1H), 3.86 (s, 3H), 3.19(d, J=6.3 Hz, 1H), 3.05 (d, J=7.5 Hz, 1H), 1.52 (s, 9H).

Preparation of (4R,5R)-4-tert-Butyl 5-methyl2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A mixture of (2R,3R)-1-tert-butyl 4-methyl 2,3-dihydroxysuccinate (2.62g, 11.9 mmol), 2,2-dimethoxypropane (2.2 mL, 18 mmol), andp-toluensulfonic acid (50 mg, 0.26 mmol) in benzene (30 mL) was stirredat reflux for 20 h. After this time, the mixture was cooled to roomtemperature, and saturated sodium bicarbonate was added. The mixture wasstirred for 5 min and then extracted with ethyl acetate. The organicextracts were washed with water and brine and then concentrated. Theresidue was purified by column chromatography (80 g silica gel column,5-70% ethyl acetate/heptane) to provide (4R,5R)-4-tert-butyl 5-methyl2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (1.63 g, 53%): ¹H NMR (300MHz, CDCl₃) δ 4.71 (d, J=5.9 Hz, 1H), 4.64 (d, J=5.9 Hz, 1H), 3.82 (s,3H), 1.50 (s, 15H).

Preparation of(4R,5R)-5-(tert-Butoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid

A solution of (4R,5R)-4-tert-butyl 5-methyl2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (4.96 g, 19.1 mmol) intetrahydrofuran (35 mL) was treated with a solution of lithium hydroxide(940 mg, 22.4 mmol) in water (15 mL), and the mixture was stirred atroom temperature for 1 h. After this time, 2N hydrochloric acid wasadded until the mixture tested neutral by pH paper analysis. The mixturewas partially concentrated and then extracted with ethyl acetate. Theorganic extracts were washed with 10% citric acid and brine, dried oversodium sulfate, filtered and concentrated to provide(4R,5R)-5-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid (2.00 g, 43%): ¹H NMR (300 MHz, CDCl₃) δ 4.80 (d, J=5.7 Hz, 1H),4.66 (d, J=5.7 Hz, 1H), 1.53 (s, 3H), 1.52 (s, 9H), 1.50 (s, 3H), CO₂Hproton not observed.

Preparation of (4R,5R)-4-tert-Butyl 5-(2,5-dioxopyrrolidin-1-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A mixture of(4R,5R)-5-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid (410 mg, 1.67 mmol) and N-hydroxysuccinimide (210 mg, 1.82 mmol) intetrahydrofuran (10 mL) was treated with N,N′-dicyclohexylcarbodiimide(380 mg, 1.84 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (20 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide (4R,5R)-4-tert-butyl5-(2,5-dioxopyrrolidin-1-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (650 mg) that was usedwithout purification: ¹H NMR (300 MHz, CDCl₃) δ 5.09 (d, J=4.9 Hz, 1H),4.87 (d, J=4.9 Hz, 1H), 2.87 (s, 4H), 1.54 (s, 3H), 1.52 (s, 3H), 1.51(s, 9H).

Preparation of (4R,5R)-4-tert-Butyl5-((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A suspension of oxycodone (280 mg, 0.901 mmol) in tetrahydrofuran (8 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (1.0 mL, 1.0 mmol). Afteraddition was complete, the mixture was stirred at −50° C. for 45 min.The mixture was treated dropwise with a solution of (4R,5R)-4-tert-butyl5-(2,5-dioxopyrrolidin-1-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (330 mg, 1.0 mmol) intetrahydrofuran (8 mL). After addition was complete, the mixture wasstirred at −50° C. for 30 min. After this time, the reaction mixture wastreated with saturated aqueous ammonium chloride (10 mL) and extractedwith ethyl acetate (3×15 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (50 gC18 column, 10-100% acetonitrile/water) and freeze dried to provide(4R,5R)-4-tert-butyl5-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (120 mg, 25%) as a whitesolid: ESI MS m/z 544 [C₂₉H₃₇NO₉+H]⁺.

Preparation of(2R,3R)-2,3-Dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of (4R,5R)-4-tert-butyl5-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (120 mg, 0.221 mmol) inmethylene chloride (1 mL) was treated with trifluoroacetic acid (1 mL)and stirred under a nitrogen atmosphere at ambient temperature for 1 h.After this time, the reaction mixture was concentrated under reducedpressure. This material was purified by reversed phase columnchromatography (50 g C18 column, 5-40% acetonitrile/water) and freezedried to provide(2R,3R)-2,3-dihydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacidtrifluoroacetic acid salt (70 mg, 71%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 12.8 (s, 1H), 9.20 (s, 1H), 6.86 (d, J=8.4 Hz,1H), 6.75 (d, J=8.4 Hz, 1H), 6.30 (s, 1H), 5.71 (s, 1H), 5.54 (dd,J=6.0, 2.1 Hz, 1H), 5.31 (s, 1H), 5.04 (s, 1H), 4.55 (s, 1H), 4.41 (s,1H), 3.75 (s, 3H), 3.64 (d, J=6.3 Hz, 1H), 3.43 (d, J=19.8 Hz, 1H),3.15-3.07 (m, 2H), 2.85 (d, J=3.3 Hz, 3H), 2.69-2.62 (m, 1H), 2.49-2.43(m, 1H), 2.32-2.26 (m, 1H), 2.07 (d, J=18.3 Hz, 1H), 1.65 (d, J=11.1 Hz,1H); ESI MS m/z 448 [C₂₂H₂₅NO₉+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate

A suspension of oxycodone (810 mg, 2.54 mmol) in tetrahydrofuran (20 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (2.8 mL, 2.8 mmol).After addition was complete, the mixture was stirred at −50° C. for 45min. The mixture was treated dropwise with a solution of(S)-2,5-dioxopyrrolidin-1-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (1.0 g,2.8 mmol) in tetrahydrofuran (15 mL). After addition was complete, themixture was stirred at −50° C. for 30 min. After this time, the reactionmixture was treated with saturated aqueous ammonium chloride (30 mL) andextracted with ethyl acetate (3×30 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by reversed phase column chromatography(50 g C18 column, 10-100% acetonitrile/water) and freeze dried toprovide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (270 mg,19%) as a white solid: ESI MS m/z 559 [C₂₉H₃₈N₂O₉+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-aminopropanoyl)oxy)propanoatetrifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (100 mg,0.181 mmol) in methylene chloride (1 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-aminopropanoyl)oxy)propanoatetrifluoroacetic acid salt (100mg, quantitative) as a clear oil: ESI MS m/z 459 [C₂₄H₃₀N₂O₇+H]⁺.

Preparation of provide (S)-tert-Butyl2-(((S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-aminopropanoyl)oxy)propanoate (85 mg, 0.15 mmol) in methylenechloride (1 mL) was treated with (S)-1-tert-butyl2-(2,5-dioxopyrrolidin-1-yl) pyrrolidine-1,2-dicarboxylate (51 mg, 0.17mmol) and N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) and stirred undera nitrogen atmosphere at ambient temperature for 15 min. After thistime, the reaction mixture was concentrated under reduced pressure. Thismaterial was purified by reversed phase column chromatography (50 g C18column, 5-40% acetonitrile/water) and freeze dried to provide(S)-tert-butyl2-(((S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate(84 mg, 85%) as a white solid: ESI MS m/z 656 [C₃₄H₄₅N₃O₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-pyrrolidine-2-carboxamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt)

A solution of (S)-tert-butyl2-(((S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate(84 mg, 0.13 mmol) in methylene chloride (1 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. This material was purified byreversed phase column chromatography (50 g C18 column, 5-40%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-pyrrolidine-2-carboxamido)propanoyl)oxy)propanoatebis(trifluoroaceticacid salt) (41 mg, 58%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ9.21 (s, 2H), 8.96 (d, J=6.6 Hz, 1H), 8.55 (s, 1H), 6.86 (d, J=8.1 Hz,1H), 6.75 (d, J=8.1 Hz, 1H), 6.30 (s, 1H), 5.59 (dd, J=6.0, 2.1 Hz, 1H),5.19 (dd, J=14, 7.2 Hz, 1H), 4.99 (s, 1H), 4.48-4.39 (m, 1H), 4.25-4.18(m, 1H), 3.76 (s, 3H), 3.66 (d, J=6.0 Hz, 1H), 3.43 (d, J=19.8 Hz, 1H),3.23-3.07 (m, 4H), 2.85 (d, J=4.5 Hz, 3H), 2.69-2.57 (m, 1H), 2.49-2.41(m, 1H), 2.33-2.26 (m, 2H), 2.06 (d, J=18 Hz, 1H), 1.93-1.84 (m, 3H),1.64 (d, J=11.1 Hz, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.41 (d, J=7.2 Hz, 3H);ESI MS m/z 556 [C₂₉H₃₇N₃O₈+H]⁺.

Preparation of(2R,3R)-2,3-Diacetoxy-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid

A solution of (3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate (1.25g, 5.78 mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. was treatedwith (S)-tert-butyl 2-hydroxypropanoate (675 mg, 4.62 mmol) followed bypyridine (0.36 mL, 4.47 mmol), and the mixture was stirred at 0° C. for1 h. After this time, the reaction mixture was diluted with ethylacetate and extracted with saturated sodium bicarbonate. The aqueousextracts were acidified with 6N hydrochloric acid and then extractedwith ethyl acetate. The organic extracts were dried over sodium sulfate,filtered, and concentrated to provide(2R,3R)-2,3-diacetoxy-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (1.66 g, quantitative): ¹H NMR (300 MHz, CDCl₃) δ 5.85 (d, J=2.6Hz, 1H), 5.83 (d, J=2.6 Hz, 1H), 5.02 (q, J=7.0 Hz, 1H), 2.19 (s, 3H),2.19 (s, 3H), 1.47-1.43 (m, 12H), CO₂H proton not observed.

Preparation of (2R,3R)-1-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate

A mixture of(2R,3R)-2,3-diacetoxy-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (1.20 g, 3.31 mmol) and N-hydroxysuccinimide (410 mg, 3.56 mmol) intetrahydrofuran (20 mL) was treated with N,N′-dicyclohexylcarbodiimide(740 mg, 3.58 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (20 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide(2R,3R)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (1.60 g) that wasused without purification: ¹H NMR (300 MHz, CDCl₃) δ 6.20 (d, J=2.7 Hz,1H), 5.95 (d, J=2.7 Hz, 1H), 5.01 (q, J=7.0 Hz, 1H), 2.84 (s, 4H), 2.26(s, 3H), 2.22 (s, 3H), 1.47-1.43 (m, 12H).

Preparation of (2R,3R)-1-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate

A suspension of oxycodone (380 mg, 1.21 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.3 mL, 1.3 mmol).After addition was complete, the mixture was stirred at −50° C. for 45min. The mixture was treated dropwise with a solution of(2S,3S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (560 mg, 1.31 mmol)in tetrahydrofuran (8 mL). After addition was complete, the mixture wasstirred at −50° C. for 30 min. After this time, the reaction mixture wastreated with saturated aqueous ammonium chloride (15 mL) and extractedwith ethyl acetate (3×15 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (50 gC18 column, 10-100% acetonitrile/water) and freeze dried to provide(2R,3R)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (57 mg, 7%) as a white solid: ESI MS m/z 660[C₃₃H₄₁NO₁₃+H]⁺.

Preparation of(S)-2-(((2R,3R)-2,3-Diacetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt

A solution of (2S,3S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (57 mg, 0.086 mmol) in methylene chloride (1 mL)was treated with trifluoroacetic acid (1 mL) and stirred under anitrogen atmosphere at ambient temperature for 1 h. After this time, thereaction mixture was concentrated under reduced pressure. This materialwas purified by reversed phase column chromatography (50 g C18 column,5-40% acetonitrile/water) and freeze dried to provide(S)-2-(((2R,3R)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacidtrifluoroacetic acid salt (45 mg, 86%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 13.2 (s, 1H), 9.17 (s, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.77(d, J=8.4 Hz, 1H), 6.35 (s, 1H), 5.87 (dd, J=13.5, 2.7 Hz, 2H), 5.57(dd, J=6.3, 2.1 Hz, 1H), 5.04 (dd, J=13.8, 1.2 Hz, 1H), 4.88 (s, 1H),3.76 (s, 3H), 3.65 (d, J=6.3 Hz, 1H), 3.41 (d, J=20.1 Hz, 1H), 3.16-3.07(m, 2H), 2.84 (d, J=3.6 Hz, 3H), 2.64-2.61 (m, 1H), 2.46-2.42 (m, 1H),2.33-2.26 (m, 1H), 2.21 (s, 3H), 2.15 (s, 3H), 2.08 (d, J=18.0 Hz, 1H),1.64 (d, J=11.1 Hz, 1H), 1.38 (d, J=7.2 Hz, 3H); ESI MS m/z 604[C₂₉H₃₃NO₁₃+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-2-acetamido-6-((tert-butoxycarbonyl)amino)hexanamido)propanoyl)oxy)propanoate

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-aminopropanoyl)oxy)propanoate (82 mg, 0.18 mmol) in methylenechloride (1 mL) was treated with (S)-2,5-dioxopyrrolidin-1-yl2-acetamido-6-((tert-butoxycarbonyl)amino)hexanoate (76 mg, 0.20 mmol)and N-ethyl-N-isopropylpropan-2-amine (0.12 mL, 0.72 mmol) and stirredunder a nitrogen atmosphere at ambient temperature for 15 min. Afterthis time, the reaction mixture was concentrated under reduced pressure.This material was purified by reversed phase column chromatography (50 gC18 column, 5-40% acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-2-acetamido-6-((tert-butoxycarbonyl)amino)hexanamido)propanoyl)oxy)propanoate(64 mg, 49%) as a white solid: ESI MS m/z 729 [C₃₇H₅₂N₄O₁₁+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-2-acetamido-6-aminohexanamido)propanoyl)oxy)propanoatebis(trifluoroaceticacid salt)

A solution of (S)-tert-butyl2-(((S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate(84 mg, 0.13 mmol) in methylene chloride (1 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. This material was purified byreversed phase column chromatography (50 g C18 column, 5-40%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-2-acetamido-6-aminohexanamido)propanoyl)oxy)propanoatebis(trifluoroaceticacid salt)(32 mg, 58%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ9.19 (s, 1H), 8.42 (d, J=6.6 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.64 (s,3H), 6.86 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.30 (s, 1H), 5.57(dd, J=6.0, 2.1 Hz, 1H), 5.15 (dd, J=14, 6.9 Hz, 1H), 4.99 (s, 1H),4.34-4.25 (m, 2H), 3.75 (s, 3H), 3.66 (d, J=6.0 Hz, 1H), 3.43 (d, J=19.8Hz, 1H), 3.16-3.07 (m, 2H), 2.85 (d, J=4.5 Hz, 3H), 2.76-2.62 (m, 2H),2.33-2.26 (m, 2H), 2.06 (d, J=18 Hz, 1H), 1.84 (s, 3H), 1.66-1.34 (m,14H); ESI MS m/z 629 [C₃₂H₄₄N₄O₉+H]⁺.

Preparation of (S)-tert-Butyl 2-hydroxypropanoate

A solution of (S)-2-hydroxypropanoic acid (5.0 g, 55 mmol) and aceticacid (1 mL) in dichloromethane (40 mL) was cooled in an ice bath andtreated dropwise with acetyl chloride (4.5 mL, 61 mmol). After additionwas complete, the mixture was stirred at ambient temperature for 16 h.After this time, the mixture was diluted with water (50 mL) andextracted with methylene chloride (2×50 mL). The combined organics werewashed with brine (50 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide (S)-2-acetoxypropanoicacid (6.0 g) as a colorless oil.

(S)-2-acetoxypropanoic acid (6.0 g, 55 mmol), tert-butyl alcohol (8.10g, 110 mmol),N,N-dimethylpyridin-4-amine (2.0 g, 16 mmol) andN,N′-dicyclohexylcarbodiimide (14.7 g, 71.5 mmol) were combined andstirred at ambient temperature for 16 h. After this time, the mixturewas filtered and concentrated under reduced pressure to provide(S)-tert-butyl 2-acetoxypropanoate (12 g) as a colorless oil.

A solution of (S)-tert-butyl 2-acetoxypropanoate (12 g, 55 mmol) inmethanol (40 mL) was cooled in an ice bath and treated with a solutionof potassium carbonate (22.8 g, 165 mmol) in water (40 mL). Afteraddition was complete, the mixture was stirred in an ice bath for 5 h.After this time, the mixture was diluted with water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organics werewashed with brine (50 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (silica gel, 0-30% ethyl acetate/heptanes) toprovide (S)-tert-butyl 2-hydroxypropanoate (1.14 g, 15% in three steps)as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 4.13 (dd, J=6.9, 5.4 Hz,1H), 2.82 (d, J=5.4 Hz, 1H), 1.49 (s, 9H), 1.37 (d, J=6.9 Hz, 3H).

Preparation of (S)-tert-Butyl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate

A solution of (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid(0.66 g, 3.8 mmol) in dichloromethane (20 mL) was treated with(S)-tert-butyl 2-hydroxypropanoate (0.50 g, 3.4mmol),N,N-dimethylpyridin-4-amine (0.13 g, 1.0 mmol) andN,N′-dicyclohexylcarbodiimide (0.85 g, 4.1 mmol). The mixture wasstirred at ambient temperature for 16 h. After this time, the mixturewas filtered and concentrated under reduced pressure. The crude residuewas purified by column chromatography (silica gel, 0-30% ethylacetate/heptanes) to provide (S)-tert-butyl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate (0.22g, 21%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 4.99 (dd, J=14.1,8.4 Hz, 1H), 4.74 (dd, J=6.6, 3.6 Hz, 1H), 3.04 (dd, J=14.1, 3.6 Hz,1H), 2.85 (dd, J=17.4, 8.4 Hz, 1H), 1.62 (s, 3H), 1.55 (s, 3H), 1.47 (d,J=6.2 Hz, 3H), 1.46 (s, 9H).

Preparation of(S)-4-(((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)oxy)-2-hydroxy-4-oxobutanoicacid

A solution of (S)-tert-butyl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate (3.07g, 10.2 mmol), acetic acid (35 mL), and water (15 mL) was heated at 60°C. for 1 h. After this time, the mixture was concentrated under reducedpressure. The residue was diluted with toluene and concentrated underreduced pressure to provide of(S)-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-2-hydroxy-4-oxobutanoicacid (2.99 g, 99%) as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 12.6(s, 1H), 5.51 (s, 1H), 4.82 (dd, J=14.1, 6.9 Hz, 1H), 4.31-4.30 (m, 1H),2.72 (dd, J=15.9, 4.5 Hz, 1H), 2.60 (dd, J=15.9, 7.8 Hz, 1H), 1.40 (s,9H), 1.36 (d, J=7.2 Hz, 3H).

Preparation of (S)-1-Benzyl 4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate

(S)-4-(((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)oxy)-2-hydroxy-4-oxobutanoicacid (0.26 g, 1.0 mmol), benzylalcohol (0.15 g, 1.2mmol),N,N-dimethylpyridin-4-amine (44 mg, 0.30 mmol), andN,N′-dicyclohexylcarbodiimide (0.30 g, 1.2 mmol) were combined andstirred in methylene chloride (10 mL) at ambient temperature for 16 h.After this time, the mixture was filtered and concentrated under reducedpressure to provide to provide (S)-1-benzyl4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl) 2-hydroxysuccinate (0.32 g) asa colorless oil.

(S)-1-Benzyl 4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl) 2-hydroxysuccinate(0.32 g, 0.91 mmol), di-tert-butyl dicarbonate (0.22 g, 1.0 mmol), and4-dimethylaminopyridine (12 mg, 0.098 mmol) were combined and stirred inmethylene chloride (10 mL) at ambient temperature for 3 h. After thistime, the mixture was concentrated under reduced pressure. The cruderesidue was purified by column chromatography (silica gel, 0-30% ethylacetate/heptanes) to provide (S)-1-benzyl4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate (0.21 g, 46% in two steps) as acolorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.32 (m, 5H), 5.41 (dd,J=8.1, 4.5 Hz, 1H), 5.26 (d, J=12 Hz, 1H), 5.14 (d, J=12 Hz, 1H), 4.96(dd, J=14.1, 7.2 Hz, 1H), 2.98-2.94 (m, 2H), 1.46 (s, 9H), 1.45 (s, 9H),1.42 (d, J=7.2 Hz, 3H).

Preparation of (S)-4-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate

A solution of (S)-1-benzyl 4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate (0.54 g, 1.2 mmol) in ethylalcohol (8 mL) was treated with palladium on carbon (10%, 0.1 g). Themixture was stirred under a hydrogen atmosphere at ambient temperaturefor 2 h. After this time, the reaction mixture was filtered andconcentrated under reduced pressure to provide(S)-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoicacid (0.5 g) as a colorless oil.

(S)-4-(((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)oxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoicacid (0.50 g, 1.2 mmol), 1-hydroxypyrrolidine-2,5-dione (0.16 g, 1.4mmol) and N,N′-dicyclohexylcarbodiimide (0.27 g, 1.3 mmol) were combinedand stirred in tetrahydrofuran (10 mL) at ambient temperature for 4 h.After this time, the mixture was filtered and concentrated under reducedpressure to provide (S)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate (0.8g) as a sticky solid, which was used without purification.

Preparation of (S)-4-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate

A suspension of oxycodone (380 mg, 1.21 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.4 mL, 1.4 mmol).After addition was complete, the mixture was stirred at −50° C. for 45min. The mixture was treated dropwise with a solution of(S)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate (610mg, 1.4 mmol) in tetrahydrofuran (8 mL). After addition was complete,the mixture was stirred at −50° C. for 30 min. After this time, thereaction mixture was treated with saturated aqueous ammonium chloride(20 mL) and extracted with ethyl acetate (3×20 mL). The combinedorganics were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude residue was purified by reversed phasecolumn chromatography (50 g C18 column, 10-100% acetonitrile/water) andfreeze dried to provide (S)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)1-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate (48 mg, 6%) as a white solid: ESIMS m/z 660 [C₃₄H₄₅NO₁₂+H]⁺.

Preparation of(S)-2-((S)-3-Hydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt

A solution of (S)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate (48 mg, 0.071 mmol) in methylenechloride (1 mL) was treated with trifluoroacetic acid (1 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 1 h. After thistime, the reaction mixture was concentrated under reduced pressure. Thismaterial was purified by reversed phase column chromatography (50 g C18column, 5-40% acetonitrile/water) and freeze dried to provide(S)-2-(((S)-3-hydroxy-4-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacidtrifluoroacetic acid salt (28 mg, 76%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 13.1 (s, 1H), 9.17 (s, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.76(d, J=8.4 Hz, 1H), 6.29 (s, 1H), 6.00 (s, 1H), 5.57 (dd, J=6.0, 1.8 Hz,1H), 4.98 (d, J=4.5 Hz, 1H), 4.96 (dd, J=14.1, 6.9 Hz, 1H), 4.54-4.50(m, 1H), 3.76 (s, 3H), 3.64 (d, J=5.7 Hz, 1H), 3.43 (d, J=20.1 Hz, 1H),3.16-3.07 (m, 2H), 2.85-2.78 (m, 5H), 2.65-2.61 (m, 1H), 2.46-2.42 (m,1H), 2.33-2.25 (m, 1H), 2.07 (d, J=18.0 Hz, 1H), 1.64 (d, J=11.1 Hz,1H), 1.40 (d, J=6.9 Hz, 3H); ESI MS m/z 504 [C₂₅H₂₉NO₁₀+H]⁺.

Preparation of(2R,3R)-2,3-Diacetoxy-4-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid

A solution of (3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate (1.85g, 8.56 mmol) in N,N-dimethylformamide (2.2 mL) at 0° C. was treatedwith (S)-benzyl 2-hydroxypropanoate (1.30 g, 7.21 mmol) followed bypyridine (0.53 mL, 6.58 mmol), and the mixture was stirred at 0° C. for1 h. After this time, the reaction mixture was diluted with ethylacetate and extracted with saturated sodium bicarbonate. The aqueouslayer was collected, carefully treated with 6N hydrochloric acid untilacidic by pH paper analysis, and then extracted with ethyl acetate. Theorganic extracts were dried over sodium sulfate, filtered andconcentrated to give(2R,3R)-2,3-diacetoxy-4-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (2.80 g, 98%): ¹H NMR (300 MHz, CDCl₃) δ 7.38-7.33 (m, 5H),5.84-5.83 (m, 2H), 5.23-5.13 (m, 3H), 2.18 (s, 3H), 2.17 (s, 3H), 1.49(d, J=7.1 Hz, 3H), CO₂H proton not observed.

Preparation of (2R,3R)-1-((S)-1-(Benzyloxy)-1-oxopropan-2-yl)4-tert-butyl 2,3-diacetoxysuccinate

A mixture of(2R,3R)-2,3-diacetoxy-4-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (2.80 g, 7.07 mmol), tert-butanol (1.8 mL, 19 mmol), and4-dimethylaminopyridine (280 mg, 2.29 mmol) in methylene chloride (16mL) at 0° C. was treated with N,N′-dicyclohexylcarbodiimide (1.70 g,8.24 mmol). The ice bath was removed, and the reaction mixture wasstirred at ambient temperature for 4 h. After this time, the mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography (80 g silica gel column,0-70% ethyl acetate/heptane) to provide(2R,3R)-1-((S)-1-(benzyloxy)-1-oxopropan-2-yl) 4-tert-butyl2,3-diacetoxysuccinate (1.38 g, 43%): ¹H NMR (300 MHz, CDCl₃) δ7.38-7.31 (m, 5H), 5.85 (d, J=2.7 Hz, 1H), 5.69 (d, J=2.7 Hz, 1H),5.23-5.13 (m, 3H), 2.17 (s, 3H), 2.16 (s, 3H), 1.49 (d, J=7.1 Hz, 3H),1.45 (s, 9H).

Preparation of(S)-2-(((2R,3R)-2,3-Diacetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoicacid

A mixture of (2R,3R)-1-((S)-1-(benzyloxy)-1-oxopropan-2-yl) 4-tert-butyl2,3-diacetoxysuccinate (1.35 g, 2.99 mmol) and palladium (5% on carbon,180 mg) in ethanol (15 mL) was stirred at room temperature under balloonpressure hydrogen for 2 h. After this time, the reaction mixture waspurged with nitrogen and filtered through diatomaceous earth. Thefiltrate was concentrated under reduced pressure to provide(S)-2-(((2R,3R)-2,3-diacetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoicacid (1.01 g, 93%): ¹H NMR (300 MHz, CDCl₃) δ 5.80 (d, J=2.7 Hz, 1H),5.69 (d, J=2.7 Hz, 1H), 5.16 (q, J=7.1 Hz, 1H), 2.18 (s, 3H), 2.17 (s,3H), 1.53 (d, J=7.1 Hz, 3H), 1.46 (s, 9H), CO₂H proton not observed.

Preparation of (2R,3R)-1-tert-Butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2,3-diacetoxysuccinate

A mixture of(S)-2-(((2R,3R)-2,3-diacetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoicacid (1.00 g, 2.76 mmol) and N-hydroxysuccinimide (350 mg, 3.04 mmol) intetrahydrofuran (20 mL) was treated with N,N′-dicyclohexylcarbodiimide(627 mg, 3.04 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (20 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide (2R,3R)-1-tert-butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2,3-diacetoxysuccinate (960 mg, 76%) that was used without purification:¹H NMR (300 MHz, CDCl₃) δ 5.82 (d, J=2.7 Hz, 1H), 5.66 (d, J=2.7 Hz,1H), 5.49 (q, J=7.1 Hz, 1H), 2.85 (s, 4H), 2.18 (s, 3H), 2.16 (s, 3H),1.67 (d, J=7.1 Hz, 3H), 1.46 (s, 9H).

Preparation of (2R,3R)-1-tert-Butyl4-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2,3-diacetoxysuccinate

A suspension of oxycodone (380 mg, 1.21 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.3 mL, 1.3 mmol).After addition was complete, the mixture was stirred at −50° C. for 45min. The mixture was treated dropwise with a solution of(2R,3R)-1-tert-butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2,3-diacetoxysuccinate (560 mg, 1.32 mmol) in tetrahydrofuran (8 mL).After addition was complete, the mixture was stirred at −50° C. for 30min. After this time, the reaction mixture was treated with saturatedaqueous ammonium chloride (15 mL) and extracted with ethyl acetate (3×15mL). The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified byreversed phase column chromatography (50 g C18 column, 10-100%acetonitrile/water) and freeze dried to provide (2R,3R)-1-tert-butyl4-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2,3-diacetoxysuccinate (103 mg, 13%) as a white solid: ESI MS m/z 660[C₃₃H₄₁NO₁₃+H]⁺.

Preparation of(2R,3R)-2,3-Diacetoxy-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of (2S,3S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (57 mg, 0.091 mmol) in methylene chloride (1 mL)was treated with trifluoroacetic acid (1 mL) and stirred under anitrogen atmosphere at ambient temperature for 1 h. After this time, thereaction mixture was concentrated under reduced pressure. This materialwas purified by reversed phase column chromatography (50 g C18 column,5-40% acetonitrile/water) and freeze dried to provide(2R,3R)-2,3-diacetoxy-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacidtrifluoroacetic acid salt (68 mg, 72%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 13.9 (s, 1H), 9.19 (s, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.75(d, J=8.1 Hz, 1H), 6.32 (s, 1H), 5.72 (d, J=3.0 Hz, 1H), 5.66-5.60 (m,2H), 5.29 (dd, J=13.8, 6.9 Hz, 1H), 5.03 (s, 1H), 3.74 (s, 3H), 3.65 (d,J=6.3 Hz, 1H), 3.41 (d, J=20.1 Hz, 1H), 3.16-3.07 (m, 2H), 2.84 (d,J=3.6 Hz, 3H), 2.64-2.61 (m, 1H), 2.46-2.42 (m, 1H), 2.33-2.26 (m, 1H),2.13 (s, 3H), 2.11 (s, 3H), 2.06 (d, J=18.0 Hz, 1H), 1.65 (d, J=11.1 Hz,1H), 1.48 (d, J=6.9 Hz, 3H); ESI MS m/z 604 [C₂₉H₃₃NO₁₃+H]⁺.

Preparation of(2R,3R)-2,3-Diacetoxy-4-(((R)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid

(R)-Di-tert-butyl 2-hydroxysuccinate (1.60 g, 6.50 mmol),(3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate (1.76 g, 8.12 mmol),pyridine (462 mg, 5.85 mmol), and N,N-dimethylformamide (4 mL) werecombined and stirred at 0° C. under a nitrogen atmosphere for 3 h. Afterthis time, saturated sodium bicarbonate (15 mL) was added, and theresulting aqueous solution was washed with ethyl acetate (10 mL). Theaqueous phase was collected and acidified to pH=3 with 6 N hydrochloricacid, and the mixture was extracted with ethyl acetate (2×20 mL). Thecombined organics were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(2R,3R)-2,3-diacetoxy-4-(((R)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid (2.28 g, 75%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.80 (d,J=2.7 Hz, 1H), 5.75 (d, J=2.4 Hz, 1H), 5.36 (dd, J=7.8, 5.1 Hz, 1H),2.78-2.74 (m, 2H), 2.21 (s, 3H), 2.19 (s, 3H), 1.46 (s, 9H), 1.44 (s,9H), CO₂H proton not observed.

Preparation of (2R,3R)-1-((R)-1,4-Di-tert-butoxy-1,4-dioxobutan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate

A solution of(2R,3R)-2,3-diacetoxy-4-(((R)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid (2.28 g, 4.93 mmol) in tetrahydrofuran (40 mL) was treated withN-hydroxysuccinimide (624 mg, 5.42 mmol) andN,N′-dicyclohexylcarbodiimide (1.12 g, 5.42 mmol) and stirred under anitrogen atmosphere for 4 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide(2R,3R)-1-((R)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (3.39 g,quantitative) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 6.14 (d,J=3.0 Hz, 1H), 5.88 (d, J=3.0 Hz, 1H), 5.38 (dd, J=8.1, 3.3 Hz, 1H),2.88-2.68 (m, 6H), 2.24 (s, 3H), 2.23 (s, 3H), 1.46 (s, 9H), 1.44 (s,9H).

Preparation of (2R,3R)-1-((R)-1,4-Di-tert-butoxy-1,4-dioxobutan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate

A suspension of oxycodone (400 mg, 1.27 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.4 mL, 1.4 mmol).After addition was complete, the mixture was stirred at −50° C. for 45min. The mixture was treated dropwise with a solution of(2R,3R)-1-((R)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (800 mg, 1.4 mmol)in tetrahydrofuran (8 mL). After addition was complete, the mixture wasstirred at −50° C. for 30 min. After this time, the reaction mixture wastreated with saturated aqueous ammonium chloride (15 mL) and extractedwith ethyl acetate (3×15 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (50 gC18 column, 10-100% acetonitrile/water) and freeze dried to provide(2R,3R)-1-((R)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (128 mg, 13%) as a white solid: ESI MS m/z 760[C₃₈H₄₉NO₁₅+H]⁺.

Preparation of(R)-2-(((2R,3R)-2,3-Diacetoxy-4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid trifluoroacetic acid salt

A solution of (2R,3R)-1-((R)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (128 mg, 0.171 mmol) in methylene chloride (1 mL)was treated with trifluoroacetic acid (1 mL) and stirred under anitrogen atmosphere at ambient temperature for 1 h. After this time, thereaction mixture was concentrated under reduced pressure. This materialwas purified by reversed phase column chromatography (50 g C18 column,5-40% acetonitrile/water) and freeze dried to provide(R)-2-(((2R,3R)-2,3-diacetoxy-4-((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacidtrifluoroacetic acid salt (65 mg, 59%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 13.5 (s, 1H), 12.7 (s, 1H), 9.17 (s, 1H), 6.88 (d, J=8.4Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.33 (s, 1H), 5.80 (dd, J=9.6, 2.7 Hz,2H), 5.57 (dd, J=6.0, 2.1 Hz, 1H), 5.35 (dd, J=7.8, 1.2 Hz, 1H), 4.89(s, 1H), 3.75 (s, 3H), 3.65 (d, J=6.3 Hz, 1H), 3.41 (d, J=20.1 Hz, 1H),3.15-3.07 (m, 2H), 2.93-2.80 (m, 5H), 2.64-2.61 (m, 1H), 2.41-2.32 (m,1H), 2.32-2.26 (m, 1H), 2.27 (s, 3H), 2.07 (s, 3H), 2.06 (d, J=18.3 Hz,1H), 1.64 (d, J=11.4 Hz, 1H); ESI MS m/z 648 [C₃₀H₃₃NO₁₅+H]⁺.

Preparation of(S)-2-(((S)-4-(tert-Butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoyl)oxy)propanoicacid

(S)-Lactic acid (280 mg, 3.11 mmol), (S)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)amino)succinate(1.00 g, 2.59 mmol), 4-(dimethylamino)pyridine (32 mg, 0.259 mmol),pyridine (248 mg, 3.11 mmol), and tetrahydrofuran (17 mL) were combinedand heated at 60° C. under a nitrogen atmosphere for 24 h. After thistime, the solvent was removed under reduced pressure, and the residuewas participated between ethyl acetate (30 mL) and 10% aqueous citricacid. The organic layer was separated and washed with water (50 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide(S)-2-(((S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoyl)oxy)propanoicacid (858 mg, 91%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.51(m, 1H), 4.58 (m, 1H), 2.96-2.69 (m, 2H), 1.55 (m, 3H), 1.45 (s, 18H),CO₂H and NH protons not observed.

Preparation of (S)-4-tert-Butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate

A solution of(S)-2-(((S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoyl)oxy)propanoicacid (858 mg, 2.37 mmol) in tetrahydrofuran (30 mL) was treated withN-hydroxysuccinimide (300 mg, 2.61 mmol) andN,N′-dicyclohexylcarbodiimide (538 mg, 2.61 mmol) and stirred at roomtemperature under a nitrogen atmosphere for 5 h. After this time, thereaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether (50 mL), and thecombined filtrate and washings were concentrated under reduced pressure.The residue was triturated with diethyl ether to provide(S)-4-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate (1.24 g, quantitative) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 5.52 (m, 1H), 4.63 (m, 1H),2.97-2.73 (m, 6H), 1.68 (m, 3H), 1.45 (s, 18H), NH proton not observed.

Preparation of (S)-4-tert-Butyl1-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate

A suspension of oxycodone (380 mg, 1.21 mmol) in tetrahydrofuran (10 mL)was cooled to −50° C. and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1.3 mL, 1.3 mmol).After addition was complete, the mixture was stirred at −50° C. for 45min. The mixture was treated dropwise with a solution of(S)-4-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate (560 mg, 1.31 mmol) intetrahydrofuran (8 mL). After addition was complete, the mixture wasstirred at −50° C. for 30 min. After this time, the reaction mixture wastreated with saturated aqueous ammonium chloride (15 mL) and extractedwith ethyl acetate (3×15 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by reversed phase column chromatography (50 gC18 column, 10-100% acetonitrile/water) and freeze dried to provide(S)-4-tert-butyl1-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate (65 mg, 8%) as a white solid:ESI MS m/z 659 [C₃₄H₄₆N₂O₁₁+H]⁺.

Preparation of(S)-3-Amino-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid bis(trifluoroacetic acid salt)

A solution of (S)-4-tert-butyl1-((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate (65 mg, 0.10 mmol) in methylenechloride (1 mL) was treated with trifluoroacetic acid (1 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 1 h. After thistime, the reaction mixture was concentrated under reduced pressure. Thismaterial was purified by reversed phase column chromatography (50 g C18column, 5-40% acetonitrile/water) and freeze dried to provide(S)-3-amino-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid bis(trifluoroacetic acid salt)(46 mg, 90%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 13.2 (s, 1H), 9.20 (s, 1H), 8.48 (s, 3H), 6.87 (d,J=8.4 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.32 (s, 1H), 5.62-5.59 (m, 1H),5.39-5.30 (m, 1H), 5.00 (d, J=7.5 Hz, 1H), 4.48-4.45 (m, 1H), 3.76 (s,3H), 3.66 (d, J=6.3 Hz, 1H), 3.44 (d, J=20.1 Hz, 1H), 3.16-3.07 (m, 2H),2.96-2.85 (m, 5H), 2.64-2.61 (m, 1H), 2.46-2.42 (m, 1H), 2.33-2.26 (m,1H), 2.07 (d, J=18.0 Hz, 1H), 1.64 (d, J=12.6 Hz, 1H), 1.55 (d, J=7.2Hz, 3H); ESI MS m/z 503 [C₂₅H₃₀N₂O₉+H]⁺.

Preparation of (S)-tert-Butyl4-((tert-butoxycarbonyl)amino)-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoate

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate bis(2,2,2-trifluoroacetate) (121 mg,0.176 mmol) and (S)-5-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (108 mg, 0.269 mmol) inmethylene chloride (3 mL) was treated with N,N-diisopropylethylamine(0.13 mL, 0.75 mmol) and stirred under a nitrogen atmosphere for 45 min.After this time, the reaction mixture was diluted with methylenechloride (15 mL) and washed with saturated aqueous ammonium chloride (10mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide (S)-tert-butyl4-((tert-butoxycarbonyl)amino)-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoate(155 mg, quantitative) as a colorless semi-solid: ESI MS m/z 744[C₃₈H₅₃N₃O₁₂+H]⁺.

Preparation of(S)-4-Amino-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoicacid bis(trifluoroacetic acid salt)

A solution of (S)-tert-butyl4-((tert-butoxycarbonyl)amino)-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoate(130 mg, 0.176 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 30 min. After this time, the reaction mixturewas concentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 5-70%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-4-Amino-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoicacid bis(trifluoroacetic acid salt)(73 mg, 51%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 12.35 (br s, 1H), 9.19 (br s, 1H), 8.61 (t, J=5.4Hz, 1H), 8.13 (br s, 3H), 6.86 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.4 Hz,1H), 6.31 (br s, 1H), 5.59 (dd, J=5.7, 1.8 Hz, 1H), 5.12 (q, J=7.2 Hz,1H), 5.00 (s, 1H), 3.76 (s, 3H), 3.75-3.71 (m, 1H), 3.66 (d, J=6.3 Hz,1H), 3.53-3.40 (m, 3H), 3.35-3.25 (m, 1H), 3.16-3.07 (m, 2H), 2.85(apparent d, J=3.6 Hz, 3H), 2.67-2.55 (m, 2H), 2.49-2.42 (m, 1H,partially obscured by solvent peak), 2.35-2.26 (m, 3H), 2.09-2.03 (m,1H), 1.95-1.89 (m, 2H), 1.64 (d, J=11.1 Hz, 1H), 1.51 (d, J=7.2 Hz, 3H);ESI MS m/z 588 [C₂₉H₃₇N₃O₁₀+H]⁺; HPLC (Method A) >99% (AUC), t_(R)=7.16min.

Preparation of (S)-tert-Butyl2-((tert-butoxycarbonyl)amino)-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoate

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate bis(2,2,2-trifluoroacetate) (123 mg,0.179 mmol) and (S)-1-tert-butyl 5-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (108 mg, 0.269 mmol) inmethylene chloride (3 mL) was treated with N,N-diisopropylethylamine(0.13 mL, 0.75 mmol) and stirred under a nitrogen atmosphere for 30 min.After this time, the reaction mixture was diluted with methylenechloride (15 mL) and washed with saturated aqueous ammonium chloride (10mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide (S)-tert-butyl2-((tert-butoxycarbonyl)amino)-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoate(151 mg, quantitative) as a colorless semi-solid: ESI MS m/z 744[C₃₈H₅₃N₃O₁₂+H]⁺.

Preparation of(S)-2-Amino-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoicacid bis(trifluoroacetic acid salt)

A solution of (S)-tert-butyl2-((tert-butoxycarbonyl)amino)-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoate(133 mg, 0.179 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 30 min. After this time, the reaction mixturewas concentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 5-70%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-2-amino-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoicacid bis(trifluoroacetic acid salt)(77 mg, 53%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 9.19 (br s, 1H), 8.26 (br s, 3H), 8.10 (t, J=5.7Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.32 (br s,1H), 5.58 (dd, J=5.7, 1.8 Hz, 1H), 5.11 (q, J=7.2 Hz, 1H), 5.00 (s, 1H),3.93 (br s, 1H), 3.75 (s, 3H), 3.66 (d, J=6.3 Hz, 1H), 3.47-3.40 (m, 2H,partially obscured by water peak), 3.36-3.27 (m, 2H), 3.16-3.07 (m, 2H),2.85 (s, 3H), 2.63-2.55 (m, 2H), 2.49-2.43 (m, 1H, partially obscured bysolvent peak), 2.34-2.17 (m, 3H), 2.09-1.93 (m, 3H), 1.64 (d, J=11.1 Hz,1H), 1.50 (d, J=7.2 Hz, 3H), CO₂H proton not observed; ESI MS m/z 588[C₂₉H₃₇N₃O₁₀+H]⁺; HPLC (Method A) >99% (AUC), t_(R)=7.23 min.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)propanoyl)oxy)propanoate

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate bis(2,2,2-trifluoroacetate) (134 mg,0.195 mmol) and (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (109 mg, 0.301 mmol)in methylene chloride (3 mL) was treated with N,N-diisopropylethylamine(0.14 mL, 0.80 mmol) and stirred under a nitrogen atmosphere for 15 min.After this time, the reaction mixture was diluted with methylenechloride (15 mL) and washed with saturated aqueous ammonium chloride (10mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)propanoyl)oxy)propanoate(156 mg, quantitative) as a colorless semi-solid: ESI MS m/z 706[C₃₈H₄₇N₃O₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-amino-3-phenylpropanamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt)

A solution of(S)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)propanoyl)oxy)propanoate(137 mg, 0.195 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 30 min. After this time, the reaction mixturewas concentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 5-70%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-amino-3-phenylpropanamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt)(80 mg, 49%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 9.18 (br s, 1H), 8.48 (t, J=5.7 Hz, 1H), 8.17 (br s,3H), 7.37-7.26 (m, 3H), 7.23-7.20 (m, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.76(d, J=8.4 Hz, 1H), 6.29 (br s, 1H), 5.58 (dd, J=6.0, 2.1 Hz, 1H), 5.09(q, J=7.2 Hz, 1H), 4.99 (s, 1H), 3.94 (br s, 1H), 3.75 (s, 3H), 3.65 (d,J=6.3 Hz, 1H), 3.45-3.40 (m, 3H, partially obscured by water peak),3.24-3.07 (m, 4H), 2.99-2.96 (m, 2H), 2.85 (apparent d, J=4.2 Hz, 3H),2.68-2.55 (m, 1H), 2.49-2.41 (m, 1H, partially obscured by solventpeak), 2.37-2.25 (m, 1H), 2.05 (apparent d, J=17.7 Hz, 1H), 1.64 (d,J=13.2 Hz, 1H), 1.52 (d, J=6.9 Hz, 3H); ESI MS m/z 606 [C₃₃H₃₉N₃O₈+H]⁺;HPLC (Method A) 99.0% (AUC), t_(R)=7.94 min.

Preparation of (S)-Methyl 2-((tert-butoxycarbonyl)oxy)-2-phenylacetate

(S)-Methyl 2-hydroxy-2-phenylacetate (30.0 g, 180 mmol), di-tert-butyldicarbonate (43.3 g, 198 mmol), and zinc acetate (3.96 g, 18.0 mmol)were combined and heated at 55° C. under a nitrogen atmosphere for 48 h.After this time, the reaction mixture was cooled to ambient temperature.The mixture was diluted with water (400 mL) and extracted with methylenechloride (3×200 mL). The combined organics were washed with brine (200mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide (S)-methyl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (39.2 g, 82%) as acolorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.37-7.32 (m, 5H), 5.80 (s,1H), 3.74 (s, 3H), 1.51 (s, 9H).

Preparation of (S)-2-((tert-Butoxycarbonyl)oxy)-2-phenylacetic acid

A solution of (S)-methyl 2-((tert-butoxycarbonyl)oxy)-2-phenylacetate(9.06 g, 34.0 mmol) in a mixture of tetrahydrofuran (106 mL) and water(53 mL) was treated with lithium hydroxide hydrate (4.30 g, 102 mmol)and stirred at ambient temperature for 3 h. After this time, thevolatiles were removed under reduced pressure. The aqueous mixture wasdiluted with water (50 mL) and extracted with diethyl ether (100 mL).The aqueous layer was cooled in an ice bath, acidified to pH ˜3 with 1 Mhydrochloric acid, and extracted with ethyl acetate (3×100 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide(S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetic acid (8.40 g, 98%) as awhite solid: ¹H NMR (500 MHz, CDCl₃) δ 7.50 (7.47 (m, 2H), 7.48-7.37 (m,3H), 5.82 (s, 1H), 1.50 (s, 9H), CO₂H proton not observed.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate

A solution of (S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetic acid (8.02g, 31.8 mmol) in tetrahydrofuran (107 mL) was treated withN-hydroxysuccinimide (4.03 g, 35.0 mmol) andN,N′-dicyclohexylcarbodiimide (7.22 g, 16.4 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (8.20 g, 74%) as a whitepowder: ¹H NMR (500 MHz, DMSO) δ 7.58-7.56 (m, 2H), 7.49-7.45 (m, 3H),6.39 (s, 1H), 2.93-2.76 (m, 4H), 1.45 (s, 9H).

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate

A suspension of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (340 mg, 0.85 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.7 mL, 1.7 mmol). After 30min, the mixture was treated dropwise with a solution of(S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (592 mg, 1.69 mmol) intetrahydrofuran (5 mL) and stirred at 0° C. for 16 h. After this time,the reaction mixture was poured into cold saturated aqueous ammoniumchloride (50 mL) and extracted with ethyl acetate (2×). The combinedorganics were washed with saturated aqueous sodium bicarbonate andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The crude residue was purified by reversed phasecolumn chromatography (50 g C18 column, 0-100% acetonitrile/water) andfreeze dried to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (173 mg, 32%) as a whitesolid and as a mixture of diastereomers: ¹H NMR (300 MHz, DMSO-d₆) δ7.54-7.51 (m, 2H), 7.46-7.44 (m, 3H), 6.90 (d, J=8.1 Hz, 0.14H), 6.87(d, J=8.1 Hz, 0.86H), 6.72 (d, J=8.4 Hz, 0.14H), 6.71 (d, J=8.1 Hz,0.86H), 5.98 (s, 0.14H), 5.97 (s, 0.86H), 5.57 (dd, J=5.4, 2.1 Hz,0.86H), 5.42-5.41 (m, 0.14H), 4.86 (s, 0.86H), 4.83 (s, 0.14H), 4.76 (brs, 1H), 3.14 (d, J=19.2 Hz, 1H), 2.86-2.84 (m, 1H), 2.69-2.61 (m, 1H),2.43-2.41 (m, 1H), 2.31 (s, 3H), 2.27-2.23 (m, 1H), 2.11-1.94 (m, 3H),1.47 (s, 1.26H), 1.46 (s, 7.74H), 1.43 (s, 9H), 1.39-1.33 (m, 1H); ESIMS m/z 636 [C₃₅H₄₁NO₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-hydroxy-2-phenylacetate hydrochloride

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (250 mg, 0.574 mmol) inmethylene chloride (1 mL) was treated with trifluoroacetic acid (1 mL)and stirred under a nitrogen atmosphere at ambient temperature for 1 h.After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 0-100% acetonitrile/water) and freezedried. The product was converted to the hydrochloride salt by dissolvingin ethyl acetate and treating with an excess of a 4 M solution ofhydrogen chloride in 1,4-dioxane. The resulting solid was collected byfiltration to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-hydroxy-2-phenylacetate hydrochloride (15 mg, 6%) as a white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.12 (br s, 1H), 7.50-7.47 (m,2H), 7.42-7.31 (m, 3H), 6.68 (d, J=8.1 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H),6.26 (d, J=5.7 Hz, 1H), 6.24 (s, 1H), 5.48-5.45 (m, 1H), 5.27 (d, J=5.4Hz, 1H), 4.87 (s, 1H), 3.61-3.60 (m, 1H), 3.40-3.34 (m, 1H), 3.07-3.01(m, 2H), 2.82 (d, J=4.5 Hz, 3H), 2.64-2.57 (m, 1H), 2.43-2.38 (m, 1H),2.28-2.18 (m, 1H), 2.09-2.03 (m, 1H), 1.62-1.58 (m, 1H); ESI MS m/z 436[C₂₅H₂₅NO₆+H]⁺.

Preparation of (S)-Methyl 2-((tert-butoxycarbonyl)oxy)propanoate

(S)-Methyl 2-hydroxypropanoate (5.01 g, 48.2 mmol), di-tert-butyldicarbonate (11.63 g, 53.29 mmol), and zinc acetate (1.05 g, 4.78 mmol)were combined and heated at 55° C. under a nitrogen atmosphere for 48 h.After this time, the reaction mixture was cooled to room temperature.The mixture was diluted with water (50 mL) and extracted with methylenechloride (2×50 mL). The combined organics were washed with brine (50mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide (S)-methyl 2-((tert-butoxycarbonyl)oxy)propanoate(8.03 g, 82%) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 4.96 (q,J=7.0 Hz, 1H), 3.77 (s, 3H), 1.52 (d, J=6.5 Hz, 3H), 1.50 (s, 9H).

Preparation of (S)-2-((tert-Butoxycarbonyl)oxy)propanoic acid

A solution of (S)-methyl 2-((tert-butoxycarbonyl)oxy)propanoate (7.00 g,34.3 mmol) in tetrahydrofuran (100 mL) and water (50 mL) was treatedwith lithium hydroxide hydrate (1.45 g, 34.5 mmol) and stirred atambient temperature for 16 h. After this time, the volatiles wereremoved under reduced pressure. The aqueous mixture was diluted withwater (50 mL) and extracted with diethyl ether (100 mL). The aqueouslayer was cooled in an ice bath, acidified to pH ˜3 with 0.5 Mhydrochloric acid, and extracted with diethyl ether (3×100 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide of(S)-2-((tert-butoxycarbonyl)oxy)propanoic acid (2.83 g, 43%) as a whitesolid: ¹H NMR (500 MHz, CDCl₃) δ 4.99 (q, J=7.0 Hz, 1H), 1.56 (d, J=7.5Hz, 3H), 1.50 (s, 9H).

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate

A solution of (S)-2-((tert-butoxycarbonyl)oxy)propanoic acid (2.83 g,14.9 mmol) in tetrahydrofuran (50 mL) was treated withN-hydroxysuccinimide (1.88 g, 16.3 mmol) andN,N′-dicyclohexylcarbodiimide (3.38 g, 16.4 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate (3.54 g, 83%) as a white powder:¹H NMR (500 MHz, CDCl₃) δ 5.24 (q, J=7.0 Hz, 1H), 2.84 (s, 4H), 1.69 (d,J=7.0 Hz, 3H), 1.51 (s, 9H).

Preparation of tert-Butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate

A mixture of oxymorphone hydrochloride (10.0 g, 29.6 mmol),triethylamine (15.0 g, 148 mmol), and pyridine (2.34 g, 29.6 mmol) intetrahydrofuran (100 mL) was treated with di-tert-butyl dicarbonate(12.9 g, 59.2 mmol) and stirred under nitrogen for 16 h. After thistime, the reaction mixture was concentrated under reduced pressure. Thecrude residue was purified by column chromatography (330 g silicacolumn, 20% methanol/methylene chloride) to provide tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (8.00 g, 67%) as a white solid: ESI MS m/z 402 [C₂₂H₂₇NO₆+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)oxy)propanoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (2.49 mL, 2.49 mmol). After30 min, the mixture was treated dropwise with a solution of(S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)oxy)propanoate (716mg, 2.49 mmol) in tetrahydrofuran (5 mL) and stirred at 0° C. for 1 h.After this time, the reaction mixture was poured into cold saturatedaqueous ammonium chloride (10 mL) and extracted with ethyl acetate (2×25mL). The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified byreversed phase column chromatography (50 g C18 column, 10-100%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)oxy)propanoate (199 mg, 28%) as a white solid:¹H NMR (300 MHz, DMSO-d₆) δ 6.88 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.4 Hz,1H), 5.58 (dd, J=5.7, 2.4 Hz, 1H), 4.99-4.92 (m, 2H), 4.78 (s, 1H), 3.15(d, J=18.9 Hz, 1H), 2.87-2.86 (m, 1H), 2.73-2.62 (m, 1H), 2.49-2.41 (m,1H), 2.32 (s, 3H), 2.29-2.23 (m, 1H), 2.12-1.95 (m, 2H), 1.47-1.22 (m,23H); ESI MS m/z 574 [C₃₀H₃₉NO₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-hydroxypropanoate trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)oxy)propanoate (110 mg, 0.192 mmol) in methylenechloride (2 mL) was treated with trifluoroacetic acid (1 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 1 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography (24 g silica column, 0-20%methanol/ethyl acetate) to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-hydroxypropanoate trifluoroacetic acid salt (9 mg, 10%) as anoff-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s, 1H), 9.19 (br s,1H), 6.67 (d, J=8.1 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 6.21 (br s, 1H),5.60-5.53 (m, 2H), 4.94 (s, 1H), 4.30-4.25 (m, 1H), 3.57 (br s, 1H),3.04-2.99 (m, 2H), 2.79 (s, 3H), 2.65-2.35 (m, 2H), 2.29-2.22 (m, 1H),2.09-2.02 (m, 1H), 1.62-1.57 (m, 1H), 1.36 (d, J=6.9 Hz, 3H), one protonobscured by solvent peaks; ESI MS m/z 374 [C₂₀H₂₃NO₆+H]⁺.

Preparation 2,5-Dioxopyrrolidin-1-yl oleate

A solution of oleic acid (1.00 g, 3.54 mmol) and N-hydroxysuccinimide(407 mg, 3.54 mmol) in tetrahydrofuran (10 mL) was treated dropwise witha solution of N,N′-dicyclohexylcarbodiimide (730 mg, 3.54 mmol) intetrahydrofuran (10 mL). The mixture was heated at 50° C. under anitrogen atmosphere for 2 h. After this time, the reaction mixture wascooled to room temperature and filtered to remove the soliddicyclohexylurea byproduct. The filtrate was concentrated under reducedpressure and dried under vacuum overnight to provide2,5-dioxopyrrolidin-1-yl oleate (3.54 g, 83%) as a white semi-solid: ¹HNMR (300 MHz, DMSO-d₆) δ 5.32 (m, 2H), 2.81 (s, 4H), 2.65 (t, J=7.2 Hz,2H), 1.99-1.95 (m, 4H), 1.63-1.95 (m, 3H), 1.24-1.18 (m, 19H), 0.85 (t,J=6.3 Hz, 3H).

Preparation of(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yloleate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (300 mg, 0.747 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (2.24 mL, 2.24 mmol). After30 min, the mixture was treated dropwise with a solution of2,5-dioxopyrrolidin-1-yl oleate (312 mg, 0.821 mmol) in tetrahydrofuran(5 mL) and stirred at 0° C. for 1 h. After this time, the reactionmixture was poured into cold saturated aqueous ammonium chloride (10 mL)and extracted with ethyl acetate (2×25 mL). The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by reversed phase columnchromatography (50 g C18 column, 10-100% acetonitrile/water) and freezedried to provide(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yloleate (50 mg, 10%) as a white solid: ESI LC/MS m/z 666 [C₄₀H₅₉NO₇+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yloleate trifluoroacetic acid salt

A solution of(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yloleate (50 mg, 0.075 mmol) in methylene chloride (1 mL) was treated withtrifluoroacetic acid (0.5 mL) and stirred under a nitrogen atmosphere atambient temperature for 75 min. After this time, the reaction mixturewas concentrated under reduced pressure. The residue was dissolved inacetonitrile/water and freeze-dried to provide(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yloleate trifluoroacetic acid salt (61 mg, quantitative) as an off-white,sticky solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s, 1H), 9.15 (br s, 1H),6.67 (d, J=8.1 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 6.22 (s, 1H), 5.51-5.49(m, 1H), 5.34-5.31 (m, 2H), 4.95 (s, 1H), 3.62-3.60 (m, 1H), 3.37 (d,J=19.8 Hz, 1H), 3.11-3.02 (m, 2H), 2.84 (d, J=4.8 Hz, 3H), 2.78-2.56 (m,1H), 2.45-2.40 (m, 3H), 3.37 (dd, J=18.0, 6.0 Hz, 1H), 2.08-1.98 (m,5H), 1.63-1.52 (m, 3H), 1.28-1.24 (br m, 20H), 0.85 (t, J=6.3 Hz, 3H);ESI MS m/z 566 [C₃₅H₅₁NO₅+H]⁺.

Preparation 2,5-Dioxopyrrolidin-1-yl stearate

A solution of stearic acid (1.00 g, 3.52 mmol) and N-hydroxysuccinimide(405 mg, 3.52 mmol) in tetrahydrofuran (15 mL) was treated dropwise witha solution of N,N′-dicyclohexylcarbodiimide (725 mg, 3.52 mmol) intetrahydrofuran (10 mL). The mixture was heated at 50° C. under anitrogen atmosphere for 2 h. After this time, the reaction mixture wascooled to room temperature and filtered to remove the soliddicyclohexylurea byproduct. The filtrate was concentrated under reducedpressure and dried under vacuum overnight to provide2,5-dioxopyrrolidin-1-yl stearate (1.45 g) as a white solid: ¹H NMR (300MHz, CDCl₃) δ 2.84 (s, 4H), 2.60 (t, J=7.5 Hz, 2H), 1.79-1.08 (m, 30H),0.88 (t, J=6.6 Hz, 3H).

Preparation of(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylstearate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (300 mg, 0.748 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.90 mL, 1.90 mmol). After30 min, the mixture was treated dropwise with a solution of2,5-dioxopyrrolidin-1-yl stearate (314 mg, 0.822 mmol) intetrahydrofuran (5 mL) and stirred at 0° C. for 1 h. After this time,the reaction mixture was poured into cold saturated aqueous ammoniumchloride (10 mL) and extracted with ethyl acetate (2×25 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified byreversed phase column chromatography (50 g C18 column, 10-100%acetonitrile/water) and freeze dried to provide(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylstearate (42 mg, 8%) as a white solid: ESI LC/MS m/z 668 [C₄₀H₆₁NO₇+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylstearate trifluoroacetic acid salt

A solution of(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylstearate (42 mg, 0.063 mmol) in methylene chloride (1 mL) was treatedwith trifluoroacetic acid (0.5 mL) and stirred under a nitrogenatmosphere at ambient temperature for 45 min. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in acetonitrile/water and freeze-dried to provide(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylstearate trifluoroacetic acid salt (41 mg, 92%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 9.14 (br s, 1H), 6.67 (d, J=8.1 Hz,1H), 6.61 (d, J=8.1 Hz, 1H), 6.21 (s, 1H), 5.52-5.49 (m, 1H), 4.95 (s,1H), 3.62-3.60 (m, 1H), 3.41-3.33 (m, 1H), 3.11-3.02 (m, 2H), 2.84 (d,J=4.8 Hz, 3H), 2.73-2.63 (m, 1H), 2.45-2.40 (m, 3H), 2.30-2.22 (m, 1H),2.08-2.03 (m, 1H), 1.63-1.54 (m, 3H), 1.33-1.24 (br m, 28H), 0.85 (t,J=6.3 Hz, 3H); ESI MS m/z 568 [C₃₅H₅₃NO₅+H]⁺.

Preparation of (S)-2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid

A solution of (S)-2-hydroxysuccinic acid (25.0 g, 186 mmol) and2-methoxypropene (71.4 mL, 746 mmol) in acetone (400 mL) at 0° C. wasslowly treated with pyridinium p-toluenesulfonate (4.68 g, 18.6 mmol).The reaction mixture was warmed to ambient temperature then heated at35° C. for overnight. After this time, the volatiles were removed underreduced pressure. The residue was triturated in heptane/ethyl acetate(150 mL, 1:1) and filtered. The filtrate was diluted with ethyl acetate(300 mL) and washed with water (150 mL). The organic layer was driedover sodium sulfate, filtered and concentrated at reduced pressure togive (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (27.9 g,86%) as a light brown solid: ¹H NMR (500 MHz, CDCl₃) δ 4.72 (apparent t,J=3.5 Hz, 1H), 3.00 (dd, J=17.0, 3.5 Hz, 1H), 2.56 (dd, J=17.0, 6.5 Hz,1H), 1.57 (s, 3H), 1.50 (s, 3H).

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)aceate

The combined organics were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-methyl 2-((tert-butoxycarbonyl)oxy)propanoate (18.5 g, quantitative)as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 4.98 (apparent t, J=4.5Hz, 1H), 3.34-3.32 (m, 2H), 2.81 (s, 4H), 1.55 (s, 3H), 1.53 (s, 3H).

Preparation of(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate and(S)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate)

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (1.00 g, 2.49 mmol) in tetrahydrofuran (15 mL) was cooled to0° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (2.75 mL, 2.75 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 25 min andthen at ambient temperature for 25 min. The mixture was re-cooled to−78° C. and (S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (900 mg, 3.32 mmol) wasadded. The mixture was allowed to warm to 0° C. over 2 h. After thistime, the mixture was treated with saturated aqueous ammonium chloride,and extracted with ethyl acetate. The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (150 g C18column, 5-100% acetonitrile/water) to provide(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (425 mg, 31%): ESIMS m/z 558 [C₂₉H₃₅NO₁₀+H]+ and(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate) (197 mg, 11%):ESI MS m/z 714 [C₃₆H₄₃NO₁₄+H]⁺.

Preparation of(S)-4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (100 mg, 0.18 mmol)in 1,4-dioxane (2.5 mL) and water (0.1 mL) was treated with hydrogenchloride (4N in 1,4-dioxane, 0.4 mL, 1.6 mmol) and stirred at ambienttemperature for 2.5 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (15.5 g C18 column, 3-25%acetonitrile/water, with 0.1% trifluoracetic acid) and freeze dried toprovide(S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt (50 mg, 46%): ¹H NMR (300 MHz, DMSO-d₆) δ12.7 (br s, 1H), 9.32 (s, 1H), 9.16 (s, 1H), 6.67 (d, J=8.1 Hz, 1H),6.62 (d, J=8.1 Hz, 1H), 6.24 (s, 1H), 5.52 (dd, J=5.9, 1.9 Hz, 1H), 4.95(s, 1H), 4.35 (dd, J=7.4, 5.0 Hz, 1H), 3.61 (d, J=8.4 Hz, 1H), 3.13-3.00(m, 2H), 2.90-2.80 (m, 4H), 2.74-2.59 (m, 2H), 2.50-2.40 (m, 1H), 2.27(dd, J=17.9, 6.1 Hz, 1H), 2.05 (d, J=17.9 Hz, 1H), 1.62 (d, J=10.9 Hz,1H), one proton obscured by solvent peaks; ESI MS m/z 418[C₂₁H₂₃NO₈+H]⁺; HPLC (Method A) 98.4% (AUC), t_(R)=6.13 min.

Preparation(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one

A solution of(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-onehydrochloride (10.0 g, 29.6 mmol) in N,N-dimethylformamide (15 mL) wastreated with imidazole (11.0 g, 163 mmol) and tert-butyldimethylsilylchloride (11.0 g, 74.0 mmol) at room temperature. After 30 min, themixture was partitioned between diethyl ether and water. The organicphase was separated and the aqueous phase was extracted with diethylether. The combined organics were dried over sodium sulfate, filtered,and concentrated under reduced pressure. The crude residue was purifiedby recrystallization in ethanol to provide(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(9.81 g, 79%) as a white solid: ESI MS m/z 416 [C₂₃H₃₃NO₄Si+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)amino)propanoate

A suspension of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (5.09 g, 12.2 mmol) in tetrahydrofuran (60 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (24.5 mL, 24.5 mmol). After30 min, the mixture was treated dropwise with a solution of(S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)amino)propanoate(7.00 g, 24.5 mmol) in tetrahydrofuran (25 mL) and stirred at 0° C. for16 h. After this time, the reaction mixture was poured into coldsaturated aqueous ammonium chloride and extracted with ethyl acetate.The combined organics were washed with saturated aqueous sodiumbicarbonate and brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)amino)propanoate (3.52 g, 49%): ESI MS m/z 587[C₃₁H₄₆N₂O₇Si+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate

A solution(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)amino)propanoate (300 mg, 0.51 mmol), inmethylene chloride (5 mL) was treated with trifluoroacetic acid (1.5 mL)and the mixture was stirred at room temperature for 1 h. After thistime, N,N-diisopropylethylamine was added slowly until the reactionmixture tested basic by pH paper analysis. The mixture was treated witha solution of (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)amino)propanoate (220 mg, 0.76 mmol) inmethylene chloride (1.5 mL) and stirred at room temperature for 1 h.After this time, the mixture was concentrated under reduced pressure.The residue was diluted with ethyl acetate and washed with 10% citricacid, saturated aqueous sodium bicarbonate, and brine. The organicextracts were dried over sodium sulfate, filtered and concentrated toprovide(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate (330 mg, 98%):ESI MS m/z 659 [C₃₄H₅₀N₂O₉Si+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-hydroxypropanamido)propanoate trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate (150 mg) inmethylene chloride (1 mL) was treated with trifluoroacetic acid (0.5 mL)and stirred at ambient temperature for 30 min. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in water (3 mL), treated with trifluoroacetic acid (0.5mL) for 1 h and then freeze dried. The crude product was purified byreversed phase column chromatography (15.5 g C18 column, 5-100%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-hydroxypropanamido)propanoate trifluoroacetic acid salt (31 mg,24%): ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 9.16 (br s, 1H), 8.10(d, J=7.1 Hz, 1H), 6.68 (d, J=8.1 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 6.24(s, 1H), 5.57-5.49 (m, 2H), 4.96 (s, 1H), 4.41-4.31 (m, 1H), 4.06-4.97(m, 1H), 3.61 (d, J=6.1 Hz, 1H), 3.36 (d, partially obscured by solventpeak, 1H), 3.11-3.01 (m, 2H), 2.84 (apparent d, J=3.9 Hz, 3H), 2.69-2.60(m, 1H), 2.43 (dd, J=13.1, 5.0 Hz, 1H), 2.27 (dd, J=18.0, 6.0 Hz, 1H),2.05 (d, J=18.0 Hz, 1H), 1.62 (d, J=10.7 Hz, 1H), 1.41 (d, J=7.2 Hz,3H), 1.22 (d, J=6.8 Hz, 3H); ESI MS m/z 445 [C₂₃H₂₈N₂O₇+H]⁺; HPLC(Method B) 97.7% (AUC), t_(R)=11.6 min.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate

A solution(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)amino)propanoate (300 mg, 0.51 mmol), inmethylene chloride (5 mL) was treated with trifluoroacetic acid (1.5 mL)and the mixture was stirred at room temperature for 1 h. After thistime, N,N-diisopropylethylamine was added slowly until the reactionmixture tested basic by pH paper analysis. The mixture was treated witha solution of (S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (208 mg, 0.77 mmol) inmethylene chloride (1.5 mL) and stirred at room temperature for 1 h.After this time, the mixture was concentrated under reduced pressure.The residue was diluted with ethyl acetate and washed with 10% citricacid, saturated aqueous sodium bicarbonate, and brine, dried over sodiumsulfate, filtered and concentrated. The crude product was purified bycolumn chromatography (12 g silica, 0-100% ethyl acetate/methylenechloride) to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate (184mg, 56%): ESI MS m/z 643 [C₃₃H₄₆N₂O₉Si+H]⁺.

Preparation of(S)-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)amino)-2-hydroxy-4-oxobutanoicacid

A mixture of(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate (183mg, 0.285 mmol), trifluoroacetic acid (0.8 mL), water (0.8 mL) andmethylene chloride (0.8 mL) was vigorously stirred at ambienttemperature for 2 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 5-30%acetonitrile/water) and freeze dried to provide(S)-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)amino)-2-hydroxy-4-oxobutanoicacid (33 mg, 24%): ¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (d, J=6.8 Hz, 1H),6.58 (d, J=8.1 Hz, 1H), 6.53 (d, J=8.1 Hz, 1H), 5.51 (dd, J=5.6, 2.5 Hz,1H), 4.83 (s, 1H), 4.37-4.27 (m, 1H), 4.22 (dd, J=8.4, 4.3 Hz, 1H), 3.10(d, J=18.9 Hz, 1H), 2.93 (d, J=5.6 Hz, 1H), 2.64 (dd, J=18.9, 5.9 Hz,1H), 2.48-2.40 (m, 2H), 2.39 (s, 3H), 2.34-1.93 (m, 5H), 1.45-1.33 (m,4H), CO₂H and three OH protons not observed; ESI MS m/z 489[C₂₄H₂₈N₂O₉+H]⁺; HPLC (Method B) 95.3% (AUC), t_(R)=10.96 min.

Preparation of (R)-Methyl 2-((tert-butoxycarbonyl)oxy)-2-phenylacetate

(R)-Methyl 2-hydroxy-2-phenylacetate (20.0 g, 120 mmol), di-tert-butyldicarbonate (34.1 g, 156 mmol), and zinc acetate (3.96 g, 18.0 mmol)were combined and heated at 55° C. overnight under a nitrogenatmosphere. After this time, the reaction mixture was cooled to roomtemperature. The mixture was diluted with water (300 mL) and extractedwith methylene chloride (3×150 mL). The combined organics were washedwith brine (150 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide (R)-methyl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (31.4 g, 98%) as acolorless oil: ¹H NMR (500 MHz, CDCl₃) δ 7.49-7.46 (m, 2H), 7.40-7.36(m, 3H), 5.80 (s, 1H), 3.74 (s, 3H), 1.51 (s, 9H).

Preparation of (R)-2-((tert-Butoxycarbonyl)oxy)-2-phenylacetic acid

A solution of (R)-methyl 2-((tert-butoxycarbonyl)oxy)-2-phenylacetate(30.0 g, 110 mmol) in a mixture of tetrahydrofuran (300 mL) and water(150 mL) was treated with lithium hydroxide hydrate (9.45 g, 220 mmol)and stirred at ambient temperature for 3 h. After this time, thevolatiles were removed under reduced pressure. The aqueous mixture wasdiluted with water (50 mL) and extracted with diethyl ether (150 mL).The aqueous layer was cooled in an ice bath, acidified to pH ˜3 with 1.0M hydrochloric acid, and extracted with ethyl acetate (3×150 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide(R)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetic acid (16.8 g, 61%) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 7.51-7.44 (m, 2H), 7.41-7.36 (m,3H), 5.25 (s, 1H), 1.51 (s, 9H), CO₂H proton not observed.

Preparation of (R)-2,5-Dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate

A solution of (R)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetic acid (7.78g, 30.8 mmol) in tetrahydrofuran (110 mL) was treated withN-hydroxysuccinimide (3.90 g, 34.0 mmol) andN,N′-dicyclohexylcarbodiimide (7.00 g, 34.0 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (R)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (8.50 g, 79%) as a whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 7.57-7.55 (m, 2H), 7.44-7.42 (m, 3H),6.15 (s, 1H), 2.80 (m, 4H), 1.52 (s, 9H).

Preparation of(R)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate

A suspension of oxycodone (0.500 g, 1.24 mmol) in tetrahydrofuran (10mL) was cooled in an ice bath and treated dropwise with a 1.0 M solutionof lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.50 mL, 1.50mmol). The mixture was stirred at 0° C. for 15 min and then treateddropwise with a solution of (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (0.522 g, 1.49 mmol) intetrahydrofuran (10 mL). The mixture was stirred at 0° C. for 1 h. Afterthis time, the reaction mixture was treated with saturated aqueousammonium chloride (50 mL) and extracted with ethyl acetate (3×75 mL).The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (silica gel, 0-6% methanol/methylene chloride) toprovide(R)-(4R,4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (0.290 g, 37%) as acolorless oil: ESI MS m/z 636 [C₃₅H₄₁NO₁₀+H]⁺.

Preparation of(R)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-hydroxy-2-phenylacetate trifluoroacetic acid salt

A solution of(R)-(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (0.100 g, 0.157 mmol) inmethylene chloride (4 mL) was treated with trifluoroacetic acid (2 mL)and stirred under a nitrogen atmosphere at ambient temperature for 1 h.After this time, the reaction mixture was concentrated under reducedpressure. The residue was triturated with diethyl ether and then freezedried from water to give(R)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-hydroxy-2-phenylacetate trifluoroacetic acid salt (0.066 g, 96%) as awhite powder: ¹H NMR (300 MHz, DMSO-d₆) δ 9.34 (s, 1H), 9.14 (br s, 1H),7.50-7.41 9 m, 2H), 7.40-7.30 9 m, 3H), 6.68 (d, J=8.1 Hz, 1H), 6.61 (d,J=8.1 Hz, 1H), 6.25 (d, J=5.4 Hz 1H), 6.21 (s, 1H), 5.32 (dd, J=23.7,3.9 Hz, 1H), 4.97 (s, 1H), 3.60 (d, J=6.0 Hz, 1H), 3.09-3.00 (m, 2H),2.83 (d, J=4.2 Hz, 3H), 2.72-2.52 (m, 1H), 2.22 (dd, J=18.3, 6.3 Hz,1H), 2.01 (d, J=17.7 Hz, 1H), 1.62 (d, J=11.1 Hz, 1H); ESI MS m/z 436[C₂₅H₂₅NO₆+H]⁺; HPLC (Method A) 96.6% (AUC), t_(R)=7.84 min.

Preparation of (S)-tert-Butyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate

A solution of (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid(7.50 g, 43.1 mmol) in methylene chloride (150 mL) was treated withN,N′-dicyclohexylcarbodiimide (10.7 g, 51.7 mmol),4-dimethylaminopyridine (1.60 g, 12.9 mmol), and tert-butyl alcohol (6.2mL, 64.7 mmol) and stirred under a nitrogen atmosphere for 2 h. Afterthis time, the reaction mixture was filtered to remove the soliddicyclohexylurea byproduct. The filtrate was concentrated under reducedpressure. The crude residue was purified by column chromatography(silica gel, 0-10% ethyl acetate/heptanes) to provide (S)-tert-butyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (7.2 g, 73%) as anoff-white solid: ¹H NMR (300 MHz, CDCl₃) δ 4.66 (dd, J=6.3, 3.9 Hz, 1H),2.84 (dd, J=16.8, 3.9 Hz, 1H), 2.72 (dd, J=16.8, 6.3 Hz, 1H), 1.63 (s,3H), 1.56 (s, 3H), 1.47 (s, 9H).

Preparation of (S)-4-tert-Butyl 1-methyl 2-hydroxysuccinate

A solution of (S)-tert-butyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (6.80 g, 29.6 mmol) inmethanol (100 mL) was cooled in an ice bath and treated portion-wiseover 10 min with anhydrous sodium methoxide (1.76 g, 32.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1.5 h. Afterthis time, the reaction mixture was treated with saturated aqueousammonium chloride (100 mL) and extracted with ethyl acetate (3×100 mL).The combined organics were dried over sodium sulfate, filtered,concentrated under reduced pressure, and dried under vacuum to provide(S)-4-tert-butyl 1-methyl 2-hydroxysuccinate (5.2 g, 86%) as a yellowoil: ¹H NMR (300 MHz, CDCl₃) δ 4.44 (dd, J=10.5, 5.4 Hz, 1H), 3.81 (s,3H), 3.22 (d, J=5.4 Hz, 1H), 2.87-2.64 (m, 2H), 1.45 (s, 9H).

Preparation of (S)-4-tert-Butyl 1-methyl2-((tert-butoxycarbonyl)oxy)succinate

A solution of (S)-4-tert-butyl 1-methyl 2-hydroxysuccinate (5.30 g, 26.0mmol) in methylene chloride (150 mL) was cooled in an ice bath under anitrogen atmosphere and treated with 4-dimethylaminopyridine (0.317 g,2.60 mmol) followed by di-tert-butyl dicarbonate (8.50 g, 40.0 mmol).After 2-3 min, the ice bath was removed, and the mixture was stirred atambient temperature for 2 h. After this time, the reaction mixture wasconcentrated under reduced pressure and purified by columnchromatography (silica gel, 0-5% ethyl acetate/heptanes) to provide(S)-4-tert-butyl 1-methyl 2-((tert-butoxycarbonyl)oxy)succinate (6.6 g,83%) as a light yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.32 (dd, J=6.9,6.0 Hz, 1H), 3.78 (s, 3H), 2.81-2.79 (m, 2H), 1.50 (s, 9H), 1.45 (s,9H).

Preparation of(S)-4-(tert-Butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoic acid

A solution of (S)-4-tert-butyl 1-methyl2-((tert-butoxycarbonyl)oxy)succinate (6.60 g, 21.7 mmol) intetrahydrofuran (74 mL) and water (37 mL) was cooled in an ice bath,treated with lithium hydroxide hydrate (1.09 g, 26.1 mmol), and stirredat 0° C. for 3 h. After this time, the reaction mixture was concentratedto remove the volatiles, acidified at 0° C. to pH ˜3, and extracted withethyl acetate (3×100 mL). The combined organics were dried over sodiumsulfate, filtered, concentrated under reduced pressure, and dried undervacuum to provide(S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoic acid (5.7g, 90%): ¹H NMR (300 MHz, CDCl₃) δ 5.32 (apparent t, J=6.0 Hz, 1H), 2.85(apparent d, J=6.0 Hz, 2H), 1.50 (s, 9H), 1.46 (s, 9H), CO₂H proton notobserved.

Preparation of (S)-4-tert-Butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)oxy)succinate

A solution of(S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoic acid (525mg, 1.81 mmol) in tetrahydrofuran (10 mL) was treated withN-hydroxysuccinimide (292 mg, 2.53 mmol) andN,N′-dicyclohexylcarbodiimide (523 mg, 2.53 mmol) and stirred under anitrogen atmosphere for 1 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with tetrahydrofuran (25 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with tetrahydrofuran (25 mL) and filtered to remove thesolids. The filtrate was concentrated under reduced pressure. Theresidue was triturated with diethyl ether and filtered to remove thesolids. The filtrate was concentrated under reduced pressure and driedunder vacuum to provide (S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)oxy)succinate (702 mg, quantitative) as a lightyellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.61 (dd, J=8.1, 4.8 Hz, 1H),2.98-2.94 (m, 2H), 2.84 (s, 4H), 1.51 (s, 9H), 1.47 (s, 9H).

Preparation of(S)-1-((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-((tert-butoxycarbonyl)oxy)succinate

A suspension of oxycodone (0.402 g, 1.00 mmol) in tetrahydrofuran (8 mL)was cooled in an ice bath and treated dropwise with a 1.0 M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (2.00 mL, 2.00mmol). The mixture was stirred at 0° C. for 15 min and then treateddropwise with a solution of (S)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate(0.465 g, 1.20 mmol) in tetrahydrofuran (8 mL). The reaction mixture wasstirred at 0° C. for 1 h. After this time, the mixture was poured intosaturated aqueous ammonium chloride (100 mL) and extracted with ethylacetate (2×100 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The cruderesidue was purified by reversed phase chromatography (150 g C18 column,10-100% acetonitrile/water) and freeze dried toprovide(S)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-((tert-butoxycarbonyl)oxy)succinate (0.078 g, 11%) as awhite solid: ESI MS m/z 674[C₃₅H₄₇NO₁₂+H]⁺.

Preparation of(S)-4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(S)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-((tert-butoxycarbonyl)oxy)succinate (0.060 g, 0.089 mmol)in methylene chloride (8 mL) was treated with trifluoroacetic acid (2.5mL) and stirred under a nitrogen atmosphere at ambient temperature for 1h. After this time, the reaction mixture was concentrated under reducedpressure. The residue obtained was triturated with diethyl ether thenfreeze dried from water to provide(S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoicacidtrifluoroacetic acid salt (0.044 g, quantitative) as a white solid:¹H NMR (300 MHz, DMSO-d₆) δ 12.43 (br s, 1H), 9.30 (s, 1H), 9.16 (br s,1H), 6.69-6.64 (m, 2H), 6.25 (s, 1H), 5.90 (s, 1H), 5.55 (s, 1H), 4.93(s, 1I-2H), 2.83 (s, 3H), 2.80-2.58 (m, 3H), 2.29-2.26 (m, 1H), 2.07 (d,J=18.0 Hz, 1H), 1.62 (d, J=13.2 Hz, 1H), two protons obscured by solventpeaks; ESI MS m/z 418[C₂₁H₂₃NO₈+H]⁺.

Preparation of (S)-tert-Butyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate

A solution of (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid(7.50 g, 43.1 mmol) in methylene chloride (150 mL) was treated withN,N′-dicyclohexylcarbodiimide (10.7 g, 51.7 mmol),4-dimethylaminopyridine (1.60 g, 12.9 mmol), and tert-butyl alcohol (6.2mL, 64.7 mmol) and stirred under a nitrogen atmosphere for 2 h. Afterthis time, the reaction mixture was filtered to remove the soliddicyclohexylurea byproduct. The filtrate was concentrated under reducedpressure. The crude residue was purified by column chromatography(silica gel, 0-10% ethyl acetate/heptanes) to provide (S)-tert-butyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (7.2 g, 73%) as anoff-white solid: ¹H NMR (300 MHz, CDCl₃) δ 4.66 (dd, J=6.3, 3.9 Hz, 1H),2.84 (dd, J=16.8, 3.9 Hz, 1H), 2.72 (dd, J=16.8, 6.3 Hz, 1H), 1.63 (s,3H), 1.56 (s, 3H), 1.47 (s, 9H).

Preparation of (S)-4-tert-Butyl 1-methyl 2-hydroxysuccinate

A solution of (S)-tert-butyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (6.80 g, 29.6 mmol) inmethanol (100 mL) was cooled in an ice bath and treated portion-wiseover 10 min with anhydrous sodium methoxide (1.76 g, 32.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1.5 h. Afterthis time, the reaction mixture was treated with saturated aqueousammonium chloride (100 mL) and extracted with ethyl acetate (3×100 mL).The combined organics were dried over sodium sulfate, filtered,concentrated under reduced pressure, and dried under vacuum to provide(S)-4-tert-butyl 1-methyl 2-hydroxysuccinate (5.2 g, 86%) as a yellowoil: ¹H NMR (300 MHz, CDCl₃) δ 4.44 (dd, J=10.5, 5.4 Hz, 1H), 3.81 (s,3H), 3.22 (d, J=5.4 Hz, 1H), 2.87-2.64 (m, 2H), 1.45 (s, 9H).

Preparation of (S)-4-tert-Butyl 1-methyl2-((tert-butoxycarbonyl)oxy)succinate

A solution of (S)-4-tert-butyl 1-methyl 2-hydroxysuccinate (5.30 g, 26.0mmol) in methylene chloride (150 mL) was cooled in an ice bath under anitrogen atmosphere and treated with 4-dimethylaminopyridine (0.317 g,2.60 mmol) followed by di-tert-butyl dicarbonate (8.50 g, 40.0 mmol).After 2-3 min, the ice bath was removed, and the mixture was stirred atambient temperature for 2 h. After this time, the reaction mixture wasconcentrated under reduced pressure and purified by columnchromatography (silica gel, 0-5% ethyl acetate/heptanes) to provide(S)-4-tert-butyl 1-methyl 2-((tert-butoxycarbonyl)oxy)succinate (6.6 g,83%) as a light yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.32 (dd, J=6.9,6.0 Hz, 1H), 3.78 (s, 3H), 2.81-2.79 (m, 2H), 1.50 (s, 9H), 1.45 (s,9H).

Preparation of(S)-4-(tert-Butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoic acid

A solution of (S)-4-tert-butyl 1-methyl2-((tert-butoxycarbonyl)oxy)succinate (6.60 g, 21.7 mmol) intetrahydrofuran (74 mL) and water (37 mL) was cooled in an ice bath,treated with lithium hydroxide hydrate (1.09 g, 26.1 mmol), and stirredat 0° C. for 3 h. After this time, the reaction mixture was concentratedto remove the volatiles, acidified at 0° C. to pH ˜3, and extracted withethyl acetate (3×100 mL). The combined organics were dried over sodiumsulfate, filtered, concentrated under reduced pressure, and dried undervacuum to provide(S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoic acid (5.7g, 90%): ¹H NMR (300 MHz, CDCl₃) δ 5.32 (apparent t, J=6.0 Hz, 1H), 2.85(apparent d, J=6.0 Hz, 2H), 1.50 (s, 9H), 1.46 (s, 9H), CO₂H proton notobserved.

Preparation of (S)-4-tert-Butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)oxy)succinate

A solution of(S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoic acid (525mg, 1.81 mmol) in tetrahydrofuran (10 mL) was treated withN-hydroxysuccinimide (292 mg, 2.53 mmol) andN,N′-dicyclohexylcarbodiimide (523 mg, 2.53 mmol) and stirred under anitrogen atmosphere for 1 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with tetrahydrofuran (25 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with tetrahydrofuran (25 mL) and filtered to remove thesolids. The filtrate was concentrated under reduced pressure. Theresidue was triturated with diethyl ether and filtered to remove thesolids. The filtrate was concentrated under reduced pressure and driedunder vacuum to provide (S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)oxy)succinate (702 mg, quantitative) as a lightyellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.61 (dd, J=8.1, 4.8 Hz, 1H),2.98-2.94 (m, 2H), 2.84 (s, 4H), 1.51 (s, 9H), 1.47 (s, 9H).

Preparation of (S)-tert-Butyl3-((tert-butoxycarbonyl)oxy)-4-(((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)amino)-4-oxobutanoate

A solution(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)amino)propanoate (500 mg, 0.85 mmol) inmethylene chloride (8 mL) was treated with trifluoroacetic acid (1.5mL), and the mixture was stirred at room temperature for 1 h. After thistime, N,N-diisopropylethylamine was added slowly until the reactionmixture tested basic by pH paper analysis. The mixture was treated witha solution of (S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)oxy)succinate (495 mg, 1.28 mmol) in methylenechloride (3 mL) and stirred at room temperature for 1 h. After thistime, the mixture was concentrated under reduced pressure. The residuewas diluted with ethyl acetate and washed with 10% citric acid,saturated aqueous sodium bicarbonate, and brine, dried over sodiumsulfate, filtered, and concentrated. The crude product was purified bycolumn chromatography (24 g silica, 0-100% ethyl acetate/methylenechloride) to provide (S)-tert-butyl3-((tert-butoxycarbonyl)oxy)-4-(((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)amino)-4-oxobutanoate(410 mg, 63%): ESI MS m/z 759 [C₃₉H₅₈N₂O₁₁Si+H]⁺.

Preparation of(S)-4-((S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)amino)-3-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt

A mixture of (S)-tert-butyl3-((tert-butoxycarbonyl)oxy)-4-(((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)amino)-4-oxobutanoate(250 mg, 0.33 mmol), trifluoroacetic acid (0.8 mL), water (0.8 mL) andmethylene chloride (0.8 mL) was vigorously stirred at ambienttemperature for 3 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 5-30%acetonitrile/water) and freeze dried to provide(S)-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)amino)-3-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt (44 mg, 27%): ¹H NMR (300 MHz, DMSO-d₆) δ8.21 (d, J=7.3 Hz, 1H), 6.57 (d, J=8.1 Hz, 1H), 6.52 (d, J=8.1 Hz, 1H),5.51 (dd, J=4.4, 2.8 Hz, 1H), 4.83 (s, 1H), 4.43-4.32 (m, 1H), 4.27 (dd,J=8.8, 3.7 Hz, 1H), 3.08 (d, J=18.6 Hz, 1H), 2.85 (d, J=5.8 Hz, 1H),2.65-2.54 (m, 2H), 2.48-2.38 (m, 1H), 2.34 (s, 3H), 2.30-2.17 (m, 2H),2.10 (d, J=8.7 Hz, 1H), 2.07-1.98 (m, 2H), 1.43-1.34 (m, 4H), CO₂H,CF₃CO₂H, and three OH protons not observed; ESI MS m/z 489[C₂₄H₂₈N₂O₉+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-3-methyl-4a-((trimethylsilyl)oxy)-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one

A suspension of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(1.20 g, 2.89 mmol) and ammonium sulfate (8 mg, 0.06 mmol) inbis(trimethylsilyl)amine (4 mL) was heated to 110° C. to obtain a clearsolution that was stirred for 6 h. After this time, the mixture wascooled to room temperature and concentrated under reduced pressure. Theresidue was suspended in 1:1 acetonitrile/water (10 mL) and acidified bydropwise addition of 2 N hydrochloric acid to obtain a clear solutionthat was stirred at room temperature for 10 min. The mixture was dilutedwith ethyl acetate and washed with a saturated solution of sodiumbicarbonate and brine. The organic layer was dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-4a-((trimethylsilyl)oxy)-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(1.23 g, 87%): ¹H NMR (300 MHz, CDCl₃) 6.61 (d, J=8.1 Hz, 1H), 6.52 (d,J=8.1 Hz, 1H), 4.50 (s, 1H), 3.17 (d, J 18.4 Hz, 1H), 3.02-2.89 (m, 2H),2.46-2.35 (m, 3H), 2.31 (s, 3H), 2.23-2.05 (m, 2H), 1.75-1.69 (m, 2H),1.41-1.35 (m, 1H), 0.99 (s, 9H), 0.27 (s, 3H), 0.18 (s, 12H).

Preparation of(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((tert-butoxycarbonyl)amino)propanoate

A suspension of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-4a-((trimethylsilyl)oxy)-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(0.26 g, 0.53 mmol) in tetrahydrofuran (8 mL) was cooled in an ice bathand treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (0.7 mL, 0.7 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled in the ice bath and treateddropwise with a solution of 2,5-dioxopyrrolidin-1-yl3-((tert-butoxycarbonyl)amino)propanoate (0.26 g, 0.91 mmol) intetrahydrofuran (4 mL). After addition was complete, the mixture wasstirred at ambient temperature for 45 min. After this time, the reactionmixture was cooled in an ice bath, treated with saturated aqueousammonium chloride, and extracted with ethyl acetate. The combinedorganics were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography (silica gel, 0-10% methanol/methylene chloride) toprovide(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((tert-butoxycarbonyl)amino)propanoate (0.20 g, 57%): ¹H NMR (300 MHz,CDCl₃) δ 6.65 (d, J=8.1 Hz, 1H), 6.55 (d, J=8.1 Hz, 1H), 5.61 (dd,J=5.6, 2.8 Hz, 1H), 5.02 (s, 1H), 3.42-3.39 (m, 2H), 3.16 (d, J=18.7 Hz,1H), 2.72-2.60 (m, 6H), 2.43 (s. 3H), 2.42-2.15 (m, 4H), 1.65-1.55 (m,1H), 1.44 (s, 9H), 9.67 (s, 9H), 0.17 (s, 3H), 0.14 (s, 3H), NH protonnot observed.

Preparation of(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate

A solution(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((tert-butoxycarbonyl)amino)propanoate (300 mg, 0.51 mmol), inmethylene chloride (5 mL) was treated with trifluoroacetic acid (1.5 mL)and the mixture was stirred at room temperature for 1 h. After thistime, N,N-diisopropylethylamine was added slowly until the reactionmixture tested basic by pH paper analysis. The mixture was treated witha solution of (S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (208 mg, 0.767 mmol) inmethylene chloride (1.5 mL) and stirred at room temperature for 1 h.After this time, the mixture was concentrated under reduced pressure.The residue was diluted with ethyl acetate and washed with 10% citricacid, saturated aqueous sodium bicarbonate, and brine, dried over sodiumsulfate, filtered and concentrated to provide(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate (372mg): ESI MS m/z 643 [C₃₃H₄₆N₂O₉Si+H]⁺.

Preparation of(S)-4-((3-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)amino)-2-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt

A mixture of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate (365mg, 0.568 mmol), trifluoroacetic acid (1 mL), water (1 mL) and methylenechloride (1 mL) was vigorously stirred at ambient temperature for 3 h.After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (150 g C18 column, 5-30% acetonitrile/water) and freezedried to provide(S)-4-((3-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)amino)-2-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt (120 mg, 48%): ¹H NMR (300 MHz, DMSO-d₆)δ 8.08 (t, J=5.6 Hz, 1H), 6.58 (d, J=8.1 Hz, 1H), 6.53 (d, J=8.1 Hz,1H), 5.53 (dd, J=5.5, 2.6 Hz, 1H), 4.85 (s, 1H), 4.22 (dd, J=8.1, 4.5Hz, 1H), 3.41-3.24 (m, 2H), 3.12 (d, J=18.8 Hz, 1H), 2.95 (d, J=6.0 Hz,1H), 2.70-2.51 (m, 4H), 2.49-4.22 (m, 1H), 2.40 (s, 3H), 2.35-1.95 (m,5H), 1.41 (d, J=12.2 Hz, 1H), CO₂H and three OH protons not observed;ESI MS m/z 489 [C₂₄H₂₈N₂O₉+H]⁺; HPLC (Method B) 97.6% (AUC), t_(R)=10.71min.

Preparation of (S)-1-tert-Butyl2-((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)pyrrolidine-1,2-dicarboxylate

A suspension of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (1.02 g, 2.45 mmol) in tetrahydrofuran (12 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (4.9 mL, 4.9 mmol). After 30min, the mixture was treated dropwise with a solution of(S)-1-tert-butyl 2-(2,5-dioxopyrrolidin-1-yl)pyrrolidine-1,2-dicarboxylate (1.5 g, 4.9 mmol) in tetrahydrofuran (6mL) and stirred at 0° C. for 16 h. After this time, the reaction mixturewas poured into cold saturated aqueous ammonium chloride and extractedwith ethyl acetate. The combined organics were washed with saturatedaqueous sodium bicarbonate and brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by reversed phase column chromatography (50 g C18 column,0-100% acetonitrile/water) and freeze dried to provide (S)-1-tert-butyl2-((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)pyrrolidine-1,2-dicarboxylate (294 mg, 20%): ESI MS m/z 613[C₃₃H₄₈N₂O₇Si+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl1-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetyl)pyrrolidine-2-carboxylate

A solution (S)-1-tert-butyl2-((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)pyrrolidine-1,2-dicarboxylate (280 mg, 0.46 mmol) in methylene chloride(5 mL) was treated with trifluoroacetic acid (1.5 mL), and the mixturewas stirred at room temperature for 1 h. After this time,N,N-diisopropylethylamine was added slowly until the reaction mixturetested basic by pH paper analysis. The mixture was treated with asolution of (S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (186 mg, 0.69 mmol) inmethylene chloride (1.5 mL) and stirred at room temperature for 1 h.After this time, the mixture was concentrated under reduced pressure.The residue was diluted with ethyl acetate and washed with 10% citricacid, saturated aqueous sodium bicarbonate, and brine, dried over sodiumsulfate, filtered and concentrated to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl1-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetyl)pyrrolidine-2-carboxylate(430 mg): ESI MS m/z 669 [C₃₅H₄₈N₂O₉Si+H]⁺.

Preparation of(S)-4-((S)-2-((((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)carbonyl)pyrrolidin-1-yl)-2-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt

A mixture of(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl1-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetyl)pyrrolidine-2-carboxylate(200 mg, 0.30 mmol), trifluoroacetic acid (0.5 mL), water (0.5 mL) andmethylene chloride (0.5 mL) was vigorously stirred at ambienttemperature for 3 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (150 g C18 column, 5-30%acetonitrile/water) and freeze dried to provide(S)-4-((S)-2-((((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)carbonyl)pyrrolidin-1-yl)-2-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt (69 mg, 36%): ¹H NMR (300 MHz, DMSO-d₆) δ6.58 (d, J=8.1 Hz, 1H), 6.53 (d, J=8.1 Hz, 1H), 5.51 (dd, J=5.5, 2.5 Hz,1H), 4.86-4.83 (m, 1H), 4.39 (dd, J=8.7, 3.5 Hz, 1H), 4.29-4.24 (m, 1H),3.65-3.54 (m, 2H), 3.10 (d, J=18.8 Hz, 1H), 2.93 (d, J=5.9 Hz, 1H),2.69-2.60 (m, 3H), 2.39 (s, 3H), 2.30-2.20 (m, 2H), 2.15 (d, J=13.4 Hz,1H), 2.10-1.92 (m, 5H), 1.40 (d, J=11.1 Hz, 1H), five protons notobserved; ESI MS m/z 515 [C₂₆H₃₀N₂O₉+H]⁺; HPLC (Method B) 95.0% (AUC),t_(R)=11.86 min.

Preparation of (2E,4E)-2,5-Dioxopyrrolidin-1-yl hexa-2,4-dienoate

A solution of (2E,4E)-hexa-2,4-dienoic acid (2.00 g, 17.8 mmol) intetrahydrofuran (50 mL) was treated with N-hydroxysuccinimide (2.26 g,19.6 mmol) and N,N′-dicyclohexylcarbodiimide (4.04 g, 19.6 mmol) andstirred under a nitrogen atmosphere for 2.5 h. After this time, thereaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether, and the combinedfiltrate and washings were concentrated under reduced pressure toprovide (2E,4E)-2,5-dioxopyrrolidin-1-yl hexa-2,4-dienoate (5.14 g,quantitative) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.53-5.44 (m,1H), 6.31-6.27 (m, 2H), 5.93 (d, J=15.3 Hz, 1H), 2.85 (s, 4H), 1.91 (d,J=5.4 Hz, 3H).

Preparation of(2E,4E)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylhexa-2,4-dienoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.50 mL, 1.50 mmol). After30 min, the mixture was treated dropwise with a solution of(2E,4E)-2,5-dioxopyrrolidin-1-yl hexa-2,4-dienoate (313 mg, 1.50 mmol)in tetrahydrofuran (5 mL) and stirred at 0° C. for 1 h. After this time,the reaction mixture was poured into cold saturated aqueous ammoniumchloride (10 mL) and extracted with ethyl acetate (2×25 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified byreversed phase column chromatography (50 g C18 column, 10-100%acetonitrile/water) and freeze dried to provide(2E,4E)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylhexa-2,4-dienoate (93 mg, 15%) as a white solid: ESI LC/MS m/z 496[C₂₈H₃₃NO₇+H]⁺.

Preparation of(2E,4E)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylhexa-2,4-dienoate trifluoroacetic acid salt

A solution of(2E,4E)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylhexa-2,4-dienoate (90 mg, 0.18 mmol) in methylene chloride (0.25 mL) wastreated with trifluoroacetic acid (0.25 mL) and stirred under a nitrogenatmosphere at ambient temperature for 1 h. After this time, the reactionmixture was concentrated under reduced pressure. The residue waspurified by reversed phase column chromatography (15 g C18 column,10-100% acetonitrile/water) and freeze dried to provide(2E,4E)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ylhexa-2,4-dienoate trifluoroacetic acid salt (51 mg, 55%) as an off-whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 9.15 (br s, 1H),7.37-7.28 (m, 1H), 6.67 (d, J=8.1 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H),6.38-6.35 (m, 2H), 6.24 (s, 1H), 5.98 (d, J=15.0 Hz, 1H), 5.59-5.57 (m,1H), 5.03 (s, 1H), 3.63-3.61 (m, 1H), 3.41-3.33 (m, 1H), 3.09-3.05 (m,2H), 2.84 (d, J=4.5 Hz, 3H), 2.67-2.60 (m, 1H), 2.49-2.41 (m, 1H),2.31-2.23 (m, 1H), 2.11-2.05 (m, 1H), 1.85 (d, J=4.5 Hz, 3H), 1.65-1.60(m, 1H); ESI MS m/z 396 [C₂₃H₂₅NO₅+H]⁺.

Preparation(S)-2-(((S)-2-((tert-Butoxycarbonyl)oxy)propanoyl)oxy)propanoic acid

A solution of (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate (1.00 g, 3.48 mmol), lactic acid(376 mg, 4.17 mmol), and 4-dimethylaminopyridine (53 mg, 0.43 mmol) intetrahydrofuran (17 mL) was treated with pyridine (0.33 g, 4.2 mmol) andheated at 50° C. under a nitrogen atmosphere for 48 h. After this time,the reaction mixture was cooled to room temperature and concentratedunder reduced pressure. The residue was dissolved in ethyl acetate (50mL) and washed with aqueous 10% citric acid (2×25 mL) and water (25 mL).The organic layer was extracted with saturated aqueous sodiumbicarbonate (2×25 mL). The combined aqueous bicarbonate layers wereacidified to pH ˜2 with 6 N hydrochloric acid and extracted with ethylacetate (4×25 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide(S)-2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoic acid(659 mg, 72%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.27-5.17(m, 1H), 4.98 (q, J=7.2 Hz, 1H), 1.60-1.55 (m, 6H), 1.50 (s, 9H), CO₂Hproton not observed; ESI MS m/z 261 [C₁₁H₁₈O₇−H]⁻.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoate

A solution of(S)-2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoic acid(659 mg, 2.51 mmol) in tetrahydrofuran (10 mL) was treated withN-hydroxysuccinimide (323 mg, 2.81 mmol) andN,N′-dicyclohexylcarbodiimide (573 mg, 2.78 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide(S)-2,5-dioxopyrrolidin-1-yl2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoate (813 g,90%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ 5.54 (q, J=6.9 Hz,1H), 4.99 (q, J=7.2 Hz, 1H), 2.84 (s, 4H), 1.72 (d, J=7.2 Hz, 3H), 1.56(d, J=6.9 Hz, 3H), 1.48 (s, 9H).

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (1.50 g, 3.79 mmol) in tetrahydrofuran (30 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (7.60 mL, 7.60 mmol). After30 min, the mixture was treated dropwise with a solution of2(S)-2,5-dioxopyrrolidin-1-yl2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoate (1.50 g,4.17 mmol) in tetrahydrofuran (15 mL) and stirred at 0° C. for 25 min.After this time, the reaction mixture was poured into cold saturatedaqueous ammonium chloride (10 mL) and extracted with ethyl acetate (2×25mL). The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified byreversed phase column chromatography (50 g C18 column, 10-100%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoate (55 mg, 2%)as a white solid: ESI LC/MS m/z 646 [C₃₃H₄₃NO₁₂+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-hydroxypropanoyl)oxy)propanoate trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)propanoate (55 mg,0.085 mmol) in methylene chloride (0.25 mL) was treated withtrifluoroacetic acid (0.25 mL) and stirred under a nitrogen atmosphereat ambient temperature for 30 min. After this time, the reaction mixturewas concentrated under reduced pressure. The residue was purified byreversed phase column chromatography (15.5 g C18 column, 10-100%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-hydroxypropanoyl)oxy)propanoate trifluoroacetic acid salt (47mg, 99%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s,1H), 9.15 (br s, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H),6.25 (br s, 1H), 5.59-5.55 (m, 1H), 5.50 (d, J=5.7 Hz, 1H), 5.15 (q,J=6.9 Hz, 1H), 4.96 (s, 1H), 4.29-4.20 (m, 1H), 3.62 (br s, 1H),3.41-3.33 (m, 1H), 3.10-3.03 (m, 2H), 2.83 (s, 3H), 2.68-2.56 (m, 1H),2.46-2.41 (m, 1H), 2.33-2.25 (m, 1H), 2.09-2.03 (m, 1H), 1.64-1.60 (m,1H), 1.53 (d, J=6.9 Hz, 3H), 1.32 (d, J=6.6 Hz, 3H); ESI MS m/z 446[C₂₃H₂₇NO₈+H]⁺.

Preparation of(S)-3-(1-(tert-Butoxycarboyl)-1H-imidazol-4-yl)-2-(3-((tert-butoxycarbonyl)amino)propanamido)propanoicacid

A suspension of (S)-2-(3-aminopropanamido)-3-(1H-imidazol-4-yl)propanoicacid (3.00 g, 13.3 mmol) in a mixture of 1,4-dioxane/water (13.5 mL,2:1) was stirred at ambient temperature until a clear solution wasobtained (˜10 minutes). The mixture was treated dropwise with a solutionof 1 M aqueous NaOH (4.40 mL, 4.42 mmol). The reaction mixture wascooled to 0° C. and treated with di-tert-butyl dicarbonate (2.12 g, 9.72mmol). The ice bath was removed and stirring continued at ambienttemperature for 2 h. After this time, the volatiles were removed underreduced pressure. The residue was diluted with water (40 mL) and ethylacetate (60 mL), acidified to pH ˜3 with 1.0 M potassium bisulfate andextracted with ethyl acetate (3×100 mL). The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure to provide(S)-3-(1-(tert-butoxycarboyl)-1H-imidazol-4-yl)-2-(3-((tert-butoxycarbonyl)amino)propanamido)propanoicacid (1.70 g, 90%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.15 (s,1H), 7.21 (s, 1H), 6.69-6.67 (br s, 1H), 5.28 (s, 1H), 4.72-4.66 (m,1H), 3.46-3.40 (m, 2H), 3.26 (dd, J=11.7, 5.7 Hz, 1H), 3.13 (dd, J=15.0,6.3 Hz, 1H), 2.46 (t, J=26.3 Hz, 2H), 1.61 (s, 9H), 1.44 (s, 9H), CO₂Hproton not observed.

Preparation of (S)-tert-Butyl4-(2-(3-((tert-butoxycarbonyl)amino)propanamido)-3-((2,5-dioxopyrrolidin-1-yl)oxy)-3-oxopropyl)-1H-imidazole-1-carboxylate

A solution of(S)-3-(1-(tert-butoxycarboyl)-1H-imidazol-4-yl)-2-(3-((tert-butoxycarbonyl)amino)propanamido)propanoicacid (4.90 g, 11.5 mmol) in tetrahydrofuran (60 mL) was treated withN-hydroxysuccinimide (1.70 g, 14.9 mmol) andN,N′-dicyclohexylcarbodiimide (3.08 g, 14.9 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-tert-butyl4-(2-(3-((tert-butoxycarbonyl)amino)propanamido)-3-((2,5-dioxopyrrolidin-1-yl)oxy)-3-oxopropyl)-1H-imidazole-1-carboxylate(7.20 g, quantitative) as a white foam: ¹H NMR (300 MHz, CDCl₃) δ 8.02(s, 1H), 7.41 (s, 1H), 5.72 (br s, 1H), 5.17-5.11 (m, 1H), 3.51-3.3.41(m, 2H), 3.21 (d, J=4.8 Hz, 2H), 2.82 (m, 5H), 2.49-2.44 (m, 2H), 1.61(s, 9H), 1.42 (s, 9H).

Preparation of tert-Butyl4-((S)-2-(3-((tert-butoxycarbonyl)amino)propanamido)-3-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)-1H-imidazole-1-carboxylate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (0.400 g, 0.996 mmol) in tetrahydrofuran (8 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (2.0 mL, 2.0 mmol). Themixture was stirred at 0° C. for 20 min and then treated dropwise with asolution of (S)-tert-butyl4-(2-(3-((tert-butoxycarbonyl)amino)propanamido)-3-((2,5-dioxopyrrolidin-1-yl)oxy)-3-oxopropyl)-1H-imidazole-1-carboxylate(1.04 g, 1.99 mmol) in tetrahydrofuran (8 mL). The reaction mixture wasstirred at 0° C. for 1.5 h. After this time, the mixture was poured intosaturated aqueous ammonium chloride (75 mL) and extracted with ethylacetate (2×100 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The cruderesidue was purified by reversed phase chromatography (150 g C18 column,10-75% acetonitrile/water) followed by regular phase chromatography(silica, 0-4% methanol/methylene chloride) to provide tert-butyl4-((S)-2-(3-((tert-butoxycarbonyl)amino)propanamido)-3-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)-1H-imidazole-1-carboxylate(0.025 g, 3%) as a white solid. This material was used without furtherpurification.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(3-aminopropanamido)-3-(1H-imidazol-4-yl)propanoate trifluoroaceticacid salt

A solution of tert-butyl4-((S)-2-(3-((tert-butoxycarbonyl)amino)propanamido)-3-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)-1H-imidazole-1-carboxylate(0.025 g, 0.03 mmol) in methylene chloride (3 mL) was treated withtrifluoroacetic acid (1.5 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was triturated withdiethyl ether then freeze dried from water to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(3-aminopropanamido)-3-(1H-imidazol-4-yl)propanoate trifluoroaceticacid salt (0.026 g, quantitative) as an off-white solid: ¹H NMR (300MHz, DMSO-d₆) δ 9.40 (br s, 1H), 9.18 (br s, 1H), 8.94 (br s, 1H), 8.82(d, J=7.2 Hz, 1H), 7.73 (br s, 3H), 7.47 (s, 1H), 6.70 (d, J=8.1 Hz,1H), 6.63 (d, J=8.1 Hz, 1H), 6.27 (s, 1H), 5.53-5.51 (m, 1H), 4.91 (s,1H), 4.69 (q, J=7.2 Hz, 1H), 3.63 (d, J=4.8 Hz, 1H), 3.39 (d, J=19.8 Hz,1H), 3.28-2.93 (m, 7H), 2.85 (s, 3H), 2.74-2.55 (m, 1H), 2.29 (dd,J=17.7, 6.0 Hz, 1H), 2.04 (d, J=18.0 Hz, 1H), three protons notobserved; ESI MS m/z 510[C₂₆H₃₁N₅O₆+H]⁺.

Preparation(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one

A solution of oxymorphone hydrochloride (10.0 g, 29.6 mmol) inN,N-dimethylformamide (15 mL) was treated with imidazole (11.0 g, 163mmol) and tert-butyldimethylsilyl chloride (11.0 g, 74.0 mmol) at roomtemperature. After 30 min, the mixture was partitioned between diethylether and water. The organic phase was separated and the aqueous phasewas extracted with diethyl ether. The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by recrystallization in ethanol to provide(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(9.81 g, 79%) as a white solid: ESI MS m/z 416 [C₂₃H₃₃NO₄Si+H]⁺.

Preparation(S)-(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)amino)propanoate

A solution of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(5.09 g, 12.2 mmol) in tetrahydrofuran (60 mL) was cooled in an ice bathand treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (24.5 mL, 24.5 mmol). After30 min, the mixture was treated dropwise with a solution of(S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)amino)propanoate(7.00 g, 24.5 mmol) in tetrahydrofuran (25 mL) and stirred at 0° C. for16 h. After this time, the reaction mixture was poured into coldsaturated aqueous ammonium chloride and extracted with ethyl acetate.The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)amino)propanoate (3.52 g, 49%) as a white solid:¹H NMR (300 MHz, CDCl₃) δ 6.65 (d, J=8.1 Hz, 1H), 6.56 (d, J=7.8 Hz,1H), 5.64 (dd, J=5.7, 2.4 Hz, 1H), 5.08 (m, 1H), 4.98 (s, 1H), 4.43 (m,1H), 3.49 (m, 1H), 3.17 (d, J=19.2 Hz, 1H), 2.73-2.10 (m, 9H), 1.67-1.58(m, 2H), 1.48 (d, J=7.2 Hz, 3H), 1.45 (s, 9H), 0.97 (s, 9H), 0.16 (s,3H), 0.14 (s, 3H).

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((tert-butoxycarbonyl)amino)propanoate (300 mg, 0.511 mmol) inmethylene chloride (2 mL) was treated with trifluoroacetic acid (0.5 mL)and stirred under a nitrogen atmosphere at ambient temperature for 1 h.The reaction mixture was then basified to pH 8-9 withN,N-diisopropylethylamine and treated with a solution of(S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (268 mg, 0.767 mmol) inmethylene chloride (1 mL). After stirring at room temperature for 2 h,the reaction mixture was washed with 10% aqueous citric acid andsaturated sodium bicarbonate. The organic phase were separated, driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by chromatography to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate (100mg, 27%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.48-7.43 (m, 2H),7.40-7.34 (m, 3H), 6.64 (d, J=8.1 Hz, 1H), 6.55 (d, J=8.1 Hz, 1H), 5.89(s, 1H), 5.64 (m, 1H), 4.96 (s, 1H), 4.72 (m, 1H), 3.19-3.13 (m, 1H),2.85 (d, J=6.3 Hz, 1H), 2.65-2.57 (m, 1H), 2.46-2.15 (m, 8H), 1.60-1.47(m, 13H), 0.96 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H), NH and OH protonsnot observed.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-hydroxy-2-phenylacetamido)propanoate trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate (100mg, 0.139 mmol) in methylene chloride (400 μL) was treated withtrifluoroacetic acid (400 μL) and stirred under a nitrogen atmosphere atambient temperature for 10 min. Water (400 μL) was added, and themixture was stirred for 21 h. After this time, the reaction mixture wasdirectly purified by reversed phase column chromatography (50 g C18column, 10-100% acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-hydroxy-2-phenylacetamido)propanoate trifluoroacetic acid salt(18 mg, 21%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s,1H), 9.17 (br s, 1H), 8.43 (d, J=7.2 Hz, 1H), 7.47-7.10 (m, 5H), 6.65(q, J=8.1 Hz, 2H), 6.27-6.23 (m, 2H), 5.48 (dd, J=6.0, 2.1 Hz, 1H), 4.95(d, J=4.5 Hz, 1H), 4.91 (s, 1H), 4.36 (m, 1H), 3.59 (m, 1H), 3.09-3.00(m, 2H), 2.82 (s, 3H), 2.72-2.38 (m, 3H), 2.28-2.20 (m, 1H), 2.06-2.00(m, 1H), 1.63-1.60 (m, 1H), 1.41 (d, J=7.2 Hz, 3H); ESI MS m/z 507[C₂₈H₃₀N₂O₇+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-3-methyl-4a-((trimethylsilyl)oxy)-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one

A suspension of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(1.20 g, 2.89 mmol) and ammonium sulfate (8 mg, 0.06 mmol) inbis(trimethylsilyl)amine (4 mL) was heated to 110° C. to obtain a clearsolution that was stirred for 6 h. After this time, the mixture wascooled to room temperature and concentrated under reduced pressure. Theresidue was suspended in 1:1 acetonitrile/water (10 mL) and acidified bydropwise addition of 2 N hydrochloric acid to obtain a clear solutionthat was stirred at room temperature for 10 min. The mixture was dilutedwith ethyl acetate and washed with a saturated solution of sodiumbicarbonate and brine. The organic layer was dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-4a-((trimethylsilyl)oxy)-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(1.23 g, 87%): ¹H NMR (300 MHz, CDCl₃) δ 6.61 (d, J=8.1 Hz, 1H), 6.52(d, J=8.1 Hz, 1H), 4.50 (s, 1H), 3.17 (d, J 18.4 Hz, 1H), 3.02-2.89 (m,2H), 2.46-2.35 (m, 3H), 2.31 (s, 3H), 2.23-2.05 (m, 2H), 1.75-1.69 (m,2H), 1.41-1.35 (m, 1H), 0.99 (s, 9H), 0.27 (s, 3H), 0.18 (s, 12H).

Preparation of(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((tert-butoxycarbonyl)amino)propanoate

A suspension of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-4a-((trimethylsilyl)oxy)-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(0.26 g, 0.53 mmol) in tetrahydrofuran (8 mL) was cooled in an ice bathand treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (0.7 mL, 0.7 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled in the ice bath and treateddropwise with a solution of 2,5-dioxopyrrolidin-1-yl3-((tert-butoxycarbonyl)amino)propanoate (0.26 g, 0.91 mmol) intetrahydrofuran (4 mL). After addition was complete, the mixture wasstirred at ambient temperature for 45 min. After this time, the reactionmixture was cooled in an ice bath, treated with saturated aqueousammonium chloride, and extracted with ethyl acetate. The combinedorganics were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography (silica gel, 0-10% methanol/methylene chloride) toprovide(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((tert-butoxycarbonyl)amino)propanoate (0.20 g, 57%): ¹H NMR (300 MHz,CDCl₃) δ 6.65 (d, J=8.1 Hz, 1H), 6.55 (d, J=8.1 Hz, 1H), 5.61 (dd,J=5.6, 2.8 Hz, 1H), 5.02 (s, 1H), 3.42-3.39 (m, 2H), 3.16 (d, J=18.7 Hz,1H), 2.72-2.60 (m, 6H), 2.43 (s. 3H), 2.42-2.15 (m, 4H), 1.65-1.55 (m,1H), 1.44 (s, 9H), 9.67 (s, 9H), 0.17 (s, 3H), 0.14 (s, 3H), NH protonnot observed.

Preparation of(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate

A solution of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((tert-butoxycarbonyl)amino)propanoate (115 mg, 0.196 mmol) inmethylene chloride (2.5 mL) was treated with trifluoroacetic acid (0.3mL), and the mixture was stirred at room temperature for 10 min. Afterthis time, LC-MS analysis of the reaction mixture showed cleavage of theBoc protecting group. N,N-Diisopropylethylamine was added slowly untilthe reaction mixture tested basic by pH paper analysis (0.4 mL of baseadded), followed by addition of (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (80 mg, 0.23 mmol) in oneportion. The reaction mixture was stirred at room temperature for 1.5 h,and then diluted with ethyl acetate; washed successively with 10% citricacid, saturated sodium bicarbonate, and brine; dried over sodiumsulfate; filtered; and concentrated. The residue was purified by columnchromatography (12 g silica, 0-10% methanol/methylene chloride) toprovide(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate (50 mg,35%): ESI MS m/z 721 [C₃₉H₅₂N₂O₉Si+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate

A solution of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate (50 mg,0.07 mmol) in tetrahydrofuran (2 mL) was treated with water (1 mL),followed by trifluoroacetic acid (1 mL), and the mixture was stirred atroom temperature for 4 h. After this time, the mixture was concentrated,and the residue was azeotroped with toluene to provide(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate (50 mg,crude) that was used without purification: ESI MS m/z 607[C₃₃H₃₈N₂O₉+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-hydroxy-2-phenylacetamido)propanoate trifluoroacetic acid salt

A solution of(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate (50 mg)in methylene chloride (1.5 mL) was treated with trifluoroacetic acid (1mL) and stirred at ambient temperature for 1 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas purified by reversed phase column chromatography (15.5 g C18 column,5-50% acetonitrile/water) and freeze dried to provide(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-hydroxy-2-phenylacetamido)propanoate trifluoroacetic acid salt(21 mg, 58% over two steps) as a fluffy white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 9.31 (s, 1H), 9.15 (s, 1H), 8.15 (t, J=5.8 Hz, 1H), 7.41-7.37(m, 2H), 7.33-7.23 (m, 3H), 6.65 (q, J=7.9 Hz, 2H), 6.22-6.20 (m, 2H),5.46 (dd, J=5.8, 1.9 Hz, 1H), 4.94 (s, 1H), 4.90 (d, J=4.5 Hz, 1H), 3.60(s, 1H), 3.40-3.32 (m, 2H), 3.13-3.00 (m, 2H), 2.83 (s, 3H), 2.62 (t,J=7.0 Hz, 3H), 2.50-2.38 (m, 1H), 2.28-2.19 (m, 1H), 2.03 (d, J=18.0 Hz,1H), 1.61 (d, J=12.3 Hz, 1H); ESI MS m/z 507 [C₃₀H₃₀F₃N₂O₈+H]⁺; HPLC(Method A) 94.9% (AUC), t_(R)=7.47 min.

Preparation of(S)-2-((3-((tert-Butoxycarbonyl)amino)propanoyl)oxy)propanoic acid

(S)-Lactic acid (755 mg, 8.38 mmol), 2,5-dioxopyrrolidin-1-yl3-((tert-butoxycarbonyl)amino)propanoate (2.00 g, 6.99 mmol),4-(dimethylamino)pyridine (85 mg, 0.70 mmol), pyridine (663 mg, 8.38mmol) and tetrahydrofuran (34 mL) were combined and heated at 80° C.under a nitrogen atmosphere for 24 h. After this time, the solvent wasremoved under reduced pressure, and the residue was partitioned betweenethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer wasseparated and extracted with saturated aqueous sodium bicarbonate (20ml). The aqueous phase was collected and acidified to pH=3 with 6 Nhydrochloric acid, and the mixture was extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide (S)-2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoicacid (1.67 g, 91%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 5.17 (q,J=6.9 Hz, 1H), 3.45 (m, 2H), 2.60 (m, 2H), 1.54 (d, J=6.9 Hz, 3H), 1.44(s, 9H).

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate

A solution of(S)-2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoic acid (1.67g, 6.40 mmol) in tetrahydrofuran (30 mL) was treated withN-hydroxysuccinimide (810 mg, 7.04 mmol) andN,N′-dicyclohexylcarbodiimide (1.45 g, 7.04 mmol) and stirred under anitrogen atmosphere for 16 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-2,5-dioxopyrrolidin-1-yl2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (2.73 g) as awhite powder: ¹H NMR (300 MHz, CDCl₃) δ 5.41 (q, J=6.9 Hz, 1H), 3.46 (m,2H), 2.85 (s, 4H), 2.64 (m, 2H), 1.69 (d, J=6.9 Hz, 3H), 1.43 (s, 9H).

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled to0° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 25 min andthen at ambient temperature for 25 min. The mixture was re-cooled to−78° C. and a solution of (S)-2,5-dioxopyrrolidin-1-yl2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (490 mg, 1.37mmol) in tetrahydrofuran (5 mL) was added. The mixture was allowed towarm to 0° C. over 2 h and then treated with saturated aqueous ammoniumchloride (10 mL), and extracted with ethyl acetate (2×25 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (40 g, silica gel, 0-20% methanol/methylenechloride, then 50 g, C18, 10-100% acetonitrile/water) to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (188 mg, 23%)as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 6.91 (d, J=8.1 Hz, 1H), 6.66(d, J=8.4 Hz, 1H), 5.63 (dd, J=5.7, 2.7 Hz, 1H), 5.17 (q, J=7.2 Hz, 1H),5.05 (s, 1H), 3.45 (m, 2H), 3.18 (d, J=18.9 Hz, 1H), 2.87 (d, J=6.3 Hz,1H), 2.59-2.69 (m, 3H), 2.47-2.01 (m, 5H), 2.38 (s, 3H), 1.53-1.67 (m,13H), 1.42 (s, 9H).

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate bis(trifluoroacetic acid salt)

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (45 mg, 0.070mmol) in methylene chloride (0.8 mL) was treated with trifluoroaceticacid (0.8 mL) and stirred under a nitrogen atmosphere at ambienttemperature for 15 min. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate bis(trifluoroacetic acid salt) (32.2mg, 68%) as a fluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s,1H), 9.16 (s, 1H), 7.78 (s, 3H), 6.66 (q, J=10.5 Hz, 2H), 6.23 (s, 1H),5.59 (dd, J=6.0, 4.2 Hz, 1H), 5.17 (q, J=6.9 Hz, 1H), 3.62 (m, 1H), 3.08(m, 4H), 2.63-2.84 (m, 6H), 2.45-2.49 (m, 4H), 2.05 (d, J=18.3 Hz, 1H),1.61 (d, J=12.3 Hz, 1H), 1.54 (d, J=6.9 Hz, 3H); ESI MS m/z 459[C₂₃H₂₈N₂O₇+H]⁺.

Preparation of(S)-2-(((S)-2-((tert-Butoxycarbonyl)amino)-4-methylpentanoyl)oxy)propanoicacid

(S)-Lactic acid (658 mg, 7.31 mmol), (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)amino)-4-methylpentanoate (2.00 g, 6.09 mmol),4-(dimethylamino)pyridine (74 mg, 0.61 mmol), pyridine (578 mg, 7.31mmol), and tetrahydrofuran (35 mL) were combined and heated at 80° C.under a nitrogen atmosphere for 24 h. After this time, the solvent wasremoved under reduced pressure, and the residue was partitioned betweenethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer wasseparated and extracted with saturated aqueous sodium bicarbonate (20ml). The aqueous phase was collected and acidified to pH=3 with 6 Nhydrochloric acid, and the mixture was extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(S)-2-(((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)oxy)propanoicacid (1.83 g, 99%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 5.20-5.14(m, 1H), 4.88 (m, 1H), 4.32 (m, 1H), 1.81-1.65 (m, 2H), 1.59-1.51 (m,4H), 1.45 (s, 9H), 0.96 (d, J=6.3 Hz, 6H), CO₂H proton not observed.

Preparation of(S)—(S)-1-((2,5-Dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl2-((tert-butoxycarbonyl)amino)-4-methylpentanoate

A solution of(S)-2-(((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)oxy)propanoicacid (1.83 g, 6.04 mmol) in tetrahydrofuran (40 mL) was treated withN-hydroxysuccinimide (765 mg, 6.64 mmol) andN,N′-dicyclohexylcarbodiimide (1.37 g, 6.64 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide(S)—(S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl2-((tert-butoxycarbonyl)amino)-4-methylpentanoate (3.03 g) as a whitesemi-solid: ¹H NMR (300 MHz, CDCl₃) δ 5.48-5.43 (m, 1H), 4.86 (m, 1H),4.38-4.33 (m, 1H), 2.84 (s, 4H), 1.91-1.48 (m, 2H), 1.72-1.70 (m, 4H),1.44 (s, 9H), 0.95 (m, 6H).

Preparation of(S)—(S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-((tert-butoxycarbonyl)amino)-4-methylpentanoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled to0° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 25 min andthen at ambient temperature for 25 min. The mixture was re-cooled to−78° C., and a solution of(S)—(S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl2-((tert-butoxycarbonyl)amino)-4-methylpentanoate (550 mg, 1.37 mmol) intetrahydrofuran (5 mL) was added. The mixture was allowed to warm to 0°C. over 2 h. After this time, the mixture was treated with saturatedaqueous ammonium chloride (10 mL) and extracted with ethyl acetate (2×25mL). The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (40 g silica gel column, 0-20% methanol/methylenechloride, then 50 g C18 column, 10-100% acetonitrile/water) to provide(S)—(S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-((tert-butoxycarbonyl)amino)-4-methylpentanoate (338 mg, 39%) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 6.89 (d, J=8.1 Hz, 1H), 6.65 (d,J=8.4 Hz, 1H), 5.61-5.60 (m, 1H), 5.20-5.16 (m, 1H), 3.19 (d, J=18.9 Hz,1H), 2.86 (d, J=6.3 Hz, 1H), 2.64 (dd, J=18.9, 6.3 Hz, 1H), 2.48-2.07(m, 5H), 2.38 (s, 3H), 1.83-1.53 (m, 6H), 1.59 (d, J=7.2 Hz, 3H), 1.54(s, 9H), 1.44 (s, 9H), 0.99-0.94 (m, 6H), OH, NH protons not observed.

Preparation of(S)—(S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-amino-4-methylpentanoate bis(trifluoroacetic acid salt)

A solution of(S)—(S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-((tert-butoxycarbonyl)amino)-4-methylpentanoate (45 mg, 0.066 mmol) inmethylene chloride (0.8 mL) was treated with trifluoroacetic acid (0.8mL) and stirred under a nitrogen atmosphere at ambient temperature for 1h. After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 0-100% acetonitrile/water) and freezedried to provide(S)—(S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-amino-4-methylpentanoate bis(trifluoroacetic acid salt) (27 mg, 58%)as a fluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.13(br s, 1H), 8.32 (br s, 3H), 6.66 (apparent q, J=9.6 Hz, 2H), 6.21 (brs, 1H), 5.60 (dd, J=6.0, 2.1 Hz, 1H), 5.34 (q, J=7.2 Hz, 1H), 4.96 (s,1H), 4.11 (t, J=6.6 Hz, 1H), 3.71-3.53 (m, 1H, partially obscured bywater peak), 3.07-3.04 (m, 2H), 2.83 (s, 3H), 2.63-2.41 (m, 3H),2.33-2.25 (m, 1H), 2.06 (d, J=18.0 Hz, 1H), 1.91-1.57 (m, 4H), 1.58 (d,J=7.2 Hz, 3H), 0.93 (t, J=6.3 Hz, 6H); ESI MS m/z 487 [C₂₆H₃₄N₂O₇+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate

A solution of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((tert-butoxycarbonyl)amino)propanoate (120 mg, 0.20 mmol) inmethylene chloride (2.5 mL) was treated with trifluoroacetic acid (0.3mL), and the mixture was stirred at room temperature for 15 min. Afterthis time, LC-MS analysis of the reaction mixture showed cleavage of theBoc protecting group. N,N-Diisopropylethylamine was added slowly untilthe reaction mixture tested basic by pH paper analysis (0.4 mL of baseadded). The mixture was treated with (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate (60 mg, 0.21 mmol) in one portionand stirred at room temperature for 2.5 h. After this time, the mixturewas diluted with ethyl acetate and washed successively with 10% citricacid, saturated sodium bicarbonate, and brine. The organic extracts weredried over sodium sulfate, filtered and concentrated. The residue waspurified by column chromatography (12 g silica, 0-10% methanol/methylenechloride) to provide(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate (60 mg, 46%):ESI MS m/z 659 [C₃₄H₅₀N₂O₉Si+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoatetrifluoroacetic acid salt

A solution of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate (58 mg, 0.088mmol) in tetrahydrofuran (2 mL) was treated with water (1 mL) followedby trifluoroacetic acid (1 mL), and the mixture was stirred at roomtemperature for 3 h. After this time, the mixture was concentrated, andthe residue was azeotroped with toluene to provide(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoatetrifluoroacetic acid salt (60 mg, crude) that was used withoutpurification: ESI MS m/z 445 [C₂₈H₃₆N₂O₉+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-hydroxypropanamido)propanoate trifluoroacetic acid salt

A solution of(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate (60 mg) inmethylene chloride (2 mL) was treated with trifluoroacetic acid (1 mL)and stirred at ambient temperature for 0.5 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas purified by reversed phase column chromatography (15.5 g C18 column,5-40% acetonitrile/water) and freeze dried to provide(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((S)-2-hydroxypropanamido)propanoate trifluoroacetic acid salt (26 mg,53% over two steps) as a fluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ9.30 (s, 1H), 9.15 (s, 1H), 7.84 (t, J=5.9 Hz, 1H), 6.67 (d, J=8.1 Hz,1H), 6.62 (d, J=8.1 Hz, 1H), 6.23 (s, 1H), 5.56-5.51 (m, 2H), 4.96 (s,1H), 4.00-3.91 (m, 1H), 3.61 (d, J=5.4 Hz, 1H), 3.42-3.31 (m, 3H),3.12-3.00 (m, 2H), 2.83 (s, 3H), 2.62 (t, J=6.9 Hz, 3H), 2.50-2.39 (m,1H), 2.26 (dd, J=17.7, 6.0 Hz, 1H), 2.06 (d, J=17.7 Hz, 1H), 1.62 (d,J=11.6 Hz, 1H), 1.20 (d, J 6.8 Hz, 3H); ESI MS m/z 445 [C₂₃H₂₈N₂O₇+H]⁺;HPLC (Method A) 97.7% (AUC), t_(R)=6.33 min.

Preparation of(S)-2-((3-((tert-Butoxycarbonyl)amino)propanoyl)oxy)-2-phenylacetic acid

(S)-Mandelic acid (1.28 g, 8.38 mmol), 2,5-dioxopyrrolidin-1-yl3-((tert-butoxycarbonyl)amino)propanoate (2.50 g, 8.73 mmol),4-(dimethylamino)pyridine (85 mg, 0.70 mmol), pyridine (663 mg, 8.38mmol), and tetrahydrofuran (34 mL) were combined and heated at 80° C.under a nitrogen atmosphere for 24 h. After this time, the solvent wasremoved under reduced pressure, and the residue was partitioned betweenethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer wasseparated and extracted with saturated aqueous sodium bicarbonate (20ml). The aqueous phase was collected and acidified to pH=3 with 6 Nhydrochloric acid, and the mixture was extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(S)-2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)-2-phenylacetic acid(2.51 g, 92%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.45 (m,2H), 7.40-7.33 (m, 3H), 6.00 (s, 1H), 3.46-3.38 (m, 2H), 2.73-2.59 (m,2H), 1.43 (s, 9H); CO₂H and NH protons not observed.

Preparation of (S)-2-((2,5-Dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate

A solution of(S)-2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)-2-phenylacetic acid(2.51 g, 7.77 mmol) in tetrahydrofuran (40 mL) was treated withN-hydroxysuccinimide (984 mg, 8.55 mmol) andN,N′-dicyclohexylcarbodiimide (1.76 g, 8.55 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate (3.51 g) as a white powder: ¹HNMR (300 MHz, CDCl₃) δ 7.54-7.53 (m, 2H), 7.46-7.44 (m, 3H), 6.32 (s,1H), 3.49-3.42 (m, 2H), 2.82 (s, 4H), 2.74-2.68 (m, 2H), 1.43 (s, 9H);NH proton not observed.

Preparation of(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled to0° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 25 min andthen at ambient temperature for 25 min. The mixture was re-cooled to−78° C., and a solution of(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate (580 mg, 1.37 mmol) intetrahydrofuran (5 mL) was added. The mixture was allowed to warm to 0°C. over 2 h. After this time, the mixture was treated with saturatedaqueous ammonium chloride (10 mL) and extracted with ethyl acetate (2×25mL). The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (40 g silica gel column, 0-20% methanol/methylenechloride, then 50 g C18 column, 10-100% acetonitrile/water) to provide(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate (176 mg, 20%) as a white solid:¹H NMR (300 MHz, CDCl₃) δ 7.54-7.51 (m, 2H), 7.45-7.36 (m, 3H), 6.91 (d,J=8.4 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 6.04 (s, 1H), 5.60 (dd, J=5.7,2.7 Hz, 1H), 4.96 (s, 1H), 3.51-3.46 (m, 2H), 3.17 (d, J=18.9 Hz, 1H),2.86-2.59 (m, 4H), 2.46-2.05 (m, 5H), 2.37 (s, 3H), 1.64-1.56 (m, 3H),1.55 (s, 9H), 1.42 (s, 9H).

Preparation of(S)-2-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-aminopropanoate bis(trifluoroacetic acid salt)

A solution of(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate (45 mg, 0.064 mmol) inmethylene chloride (0.8 mL) was treated with trifluoroacetic acid (0.8mL) and stirred under a nitrogen atmosphere at ambient temperature for 1h. After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 0-100% acetonitrile/water) and freezedried to provide(S)-2-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-aminopropanoate bis(trifluoroacetic acid salt) (33 mg, 71%) as afluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.13 (s,1H), 7.79 (s, 3H), 7.59-7.56 (m, 2H), 7.49-7.47 (m, 3H), 6.64 (q, J=11.4Hz, 2H), 6.23 (s, 1H), 6.15 (s, 1H), 5.59 (dd, J=6.0, 2.1 Hz, 1H), 4.87(s, 1H), 3.61 (m, 1H), 3.10 (m, 4H), 2.85-2.83 (m, 5H), 2.65-2.43 (m,3H), 2.29-2.21 (m, 1H), 2.06 (d, J=18.3 Hz, 1H), 1.62-1.58 (m, 1H); ESIMS m/z 507 [C₂₈H₃₀N₂O₇+H]⁺; HPLC (Method A) 98.2% (AUC), t_(R)=7.30 min.

Preparation of(S)-2-(((S)-2-((tert-Butoxycarbonyl)amino)-3-phenylpropanoyl)oxy)propanoicacid

(S)-Lactic acid (597 mg, 6.62 mmol), (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (2.00 g, 5.52 mmol),4-(dimethylamino)pyridine (67 mg, 0.552 mmol), pyridine (437 mg, 5.52mmol), and tetrahydrofuran (35 mL) were combined and heated at 80° C.under a nitrogen atmosphere for 24 h. After this time, the solvent wasremoved under reduced pressure, and the residue was partitioned betweenethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer wasseparated and extracted with saturated aqueous sodium bicarbonate (20ml). The aqueous phase was collected and acidified to pH=3 with 6 Nhydrochloric acid, and the mixture was extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(S)-2-(((S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoyl)oxy)propanoicacid (2.02 g, quantitative) as a colorless semi-solid: ¹H NMR (300 MHz,CDCl₃) δ 7.34-7.18 (m, 5H), 5.24-5.19 (m, 1H), 4.90 (m, 1H), 4.61 (m,1H), 3.25 (dd, J=14.1, 8.7 Hz, 1H), 3.07 (m, 1H), 1.55 (d, J=8.7 Hz,3H), 1.39 (s, 9H), CO₂H proton not observed.

Preparation of(S)—(S)-1-((2,5-Dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate

A solution of(S)-2-(((S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoyl)oxy)propanoicacid (2.02 g, 5.99 mmol) in tetrahydrofuran (40 mL) was treated withN-hydroxysuccinimide (759 mg, 6.59 mmol) andN,N′-dicyclohexylcarbodiimide (1.36 g, 6.59 mmol) and stirred under anitrogen atmosphere for 6 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide(S)—(S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (2.36 g) as a whitepowder: ¹H NMR (300 MHz, CDCl₃) δ 7.33-7.18 (m, 5H), 5.50 (q, J=6.9 Hz,1H), 4.89 (m, 1H), 4.74 (m, 1H), 3.25 (dd, J=14.4, 5.4 Hz, 1H), 3.03 (m,1H), 2.84 (s, 4H), 1.69 (d, J=7.2 Hz, 3H), 1.41 (s, 9H).

Preparation of(S)—(S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled to −45° C. and treated dropwisewith a solution of(S)—(S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (543 mg, 1.37 mmol) intetrahydrofuran (5 mL). After addition was complete, the mixture waswarmed to 0° C. After this time, the reaction mixture was treated withsaturated aqueous ammonium chloride (10 mL) and extracted with ethylacetate (2×25 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)—(S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (223 mg, 24%) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 7.33-7.24 (m, 5H), 6.91 (d, J=8.1Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 5.62 (m, 1H), 5.60 (q, J=6.9 Hz, 1H),5.10 (s, 1H), 5.05-4.96 (m, 1H), 4.62 (m, 1H), 3.32-3.23 (m, 1H), 3.19(d, J=19.2 Hz, 1H), 3.01 (m, 1H), 2.87 (d, J=6.3 Hz, 1H), 2.65 (dd,J=18.9, 6.0 Hz, 1H), 2.47-2.09 (m, 4H), 2.38 (s, 3H), 1.74-1.58 (m, 4H),1.53 (s, 9H), 1.38 (s, 9H), OH, NH protons not observed.

Preparation of(S)—(S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-amino-3-phenylpropanoate bis(trifluoroacetic acid salt)

A solution of(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl3-((tert-butoxycarbonyl)amino)propanoate (50 mg, 0.069 mmol) inmethylene chloride (0.8 mL) was treated with trifluoroacetic acid (0.8mL) and stirred under a nitrogen atmosphere at ambient temperature for 2h. After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 0-100% acetonitrile/water) and freezedried to provide(S)—(S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-amino-3-phenylpropanoate bis(trifluoroacetic acid salt) (27 mg, 48%)as a fluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.15(s, 1H), 8.35 (s, 3H), 7.35-7.27 (m, 5H), 6.66 (apparent q, J=9.6 Hz,2H), 6.24 (s, 1H), 5.59 (dd, J=6.0, 2.1 Hz, 1H), 5.30 (q, J=7.2 Hz, 1H),4.97 (s, 1H), 4.44 (t, J=6.6 Hz, 1H), 3.62 (m, 1H), 3.25-3.05 (m, 5H),2.84 (s, 3H), 2.64 (m, 1H), 2.29-2.26 (m, 1H), 2.07 (d, J=18.3 Hz, 1H),1.64-1.61 (m, 1H), 1.51 (d, J=6.9 Hz, 3H), one proton obscured bysolvent peaks; ESI MS m/z 521 [C₂₉H₃₂N₂O₇+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate dihydrochloride

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (45 mg, 0.070mmol) in ethyl acetate (0.8 mL) was treated with a 4.0 M solution ofhydrogen chloride in 1,4-dioxane (0.5 mL) and stirred under a nitrogenatmosphere at ambient temperature for 30 min. After this time, thereaction mixture was filtered and the filter cake was collected anddried under vacuum to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate dihydrochloride (47 mg, 100%) as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 9.20 (s, 1H),7.91 (s, 3H), 6.66 (apparent q, J=8.1 Hz, 2H), 6.27 (s, 1H), 5.59 (m,1H), 5.17 (q, J=7.5 Hz, 1H), 4.96 (s, 1H), 3.11-3.03 (m, 2H), 2.85-2.76(m, 6H), 2.46-2.27 (m, 2H), 2.06 (m, 1H), 1.60-1.46 (m, 8H).

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoyl)oxy)propanoate

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate dihydrochloride (47 mg, 0.070 mmol)in tetrahydrofuran (2 mL) was treated with (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate (20 mg, 0.070 mmol) andN,N-diisopropylethylamine (18 mg, 0.024 mmol) at 0° C. and stirred undera nitrogen atmosphere for 1 h. After this time the reaction mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (40 g silica gel column, 0-20% methanol/methylenechloride) to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoyl)oxy)propanoate(52 mg) as a white solid. ESI MS m/z 617 [C₃₁H₄₀N₂O₁₁+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-hydroxypropanamido)propanoyl)oxy)propanoate trifluoroaceticacid salt

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoyl)oxy)propanoate(52 mg, 0.084 mmol) in methylene chloride (0.8 mL) was treated withtrifluoroacetic acid (0.8 mL) and stirred under a nitrogen atmosphere atambient temperature for 2 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-hydroxypropanamido)propanoyl)oxy)propanoate trifluoroaceticacid salt (22 mg, 49%) as a fluffy white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 9.28 (s, 1H), 9.15 (s, 1H), 7.79 (t, J=6.0 Hz, 1H), 6.65(apparent q, J=8.4 Hz, 1H), 6.25 (s, 1H), 5.58 (dd, J=6.0, 2.1 Hz, 1H),5.11 (q, J=7.2 Hz, 1H), 4.96 (s, 1H), 3.94 (m, 1H), 3.62 (m, 1H), 3.38(m, 4H), 3.05 (m, 2H), 2.83 (s, 3H), 2.64 (m, 1H), 2.57 (t, J=6.9 Hz,2H), 2.42 (m, 2H), 2.29 (m, 1H), 2.06 (d, J=18.0 Hz, 1H), 1.63 (d,J=11.4 Hz, 1H), 1.52 (d, J=9.6 Hz, 3H), 1.19 (d, J=9.6 Hz, 3H); ESI MSm/z 517 [C₂₆H₃₂N₂O₉+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((tert-butoxycarbonyl)amino)propanoate)

A solution of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(1.07 g, 2.57 mmol) in tetrahydrofuran (15 mL) was cooled in an ice bathand treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (4.6 mL, 4.6 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to −40° C. and treated dropwisewith a solution of 2,5-dioxopyrrolidin-1-yl3-((tert-butoxycarbonyl)amino)propanoate (1.30 g, 4.54 mmol) intetrahydrofuran (6 mL). After addition was complete, the mixture wasstirred at −40° C. for 20 min and then at ambient temperature for 40min. After this time, the reaction mixture was cooled in an ice bath,treated with saturated aqueous ammonium chloride, and extracted withethyl acetate. The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, 0-10% methanol/methylenechloride) to provide(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((tert-butoxycarbonyl)amino)propanoate) (1.0 g, 66%): ESI MS m/z758 [C₃₉H₅₉N₃O₁₀Si+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate)

A solution of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((tert-butoxycarbonyl)amino)propanoate) (255 mg, 0.336 mmol) inmethylene chloride (5 mL) was treated with trifluoroacetic acid (0.5mL), and the mixture was stirred at room temperature for 30 min. Afterthis time, LC-MS analysis of the reaction mixture showed cleavage of theBoc protecting groups. N,N-Diisopropylethylamine was added slowly untilthe reaction mixture tested basic by pH paper analysis (1 mL of baseadded). The mixture was treated with (S)-2,5-dioxo phenylacetate (330mg, 1.32 mmol) in one portion and stirred at room temperature for 2 h.After this time, the mixture was diluted with ethyl acetate and washedwater. The organic extracts were dried over sodium sulfate, filtered,and concentrated. The residue was purified by reversed phase columnchromatography (50 g C18 column, 5-100% acetonitrile/water) to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate)(254 mg, 73%): ESI MS m/z 1026 [C₅₅H₇₁N₃O₁₄Si+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-Hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate)trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate)(250 mg, 0.24 mmol) in tetrahydrofuran (6 mL) was treated with water (4mL) followed by trifluoroacetic acid (3 mL), and the mixture was stirredat room temperature for 3 h. After this time, the mixture wasconcentrated, and the residue was azeotroped with toluene to provide(S)-(4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate)trifluoroacetic acid salt (270 mg, crude) that was used withoutpurification: ESI MS m/z 912 [C₄₉H₅₇N₃O₁₄+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-Hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-hydroxy-2-phenylacetamido)propanoate) trifluoroacetic acidsalt

A solution of(S)-(4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)propanoate)(270 mg) in methylene chloride (6 mL) was treated with trifluoroaceticacid (2 mL) and stirred at ambient temperature for 40 min. After thistime, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 5-30% acetonitrile/water, with 0.1% trifluoroacetic acid) andfreeze dried to provide(S)-(4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-hydroxy-2-phenylacetamido)propanoate) trifluoroacetic acidsalt (147 mg, 69% over two steps) as a fluffy white solid: ¹H NMR (300MHz, DMSO-d₆) δ 9.46 (broad s, 1.5H), 8.24-8.15 (m, 2H), 7.41-7.20 (m,10H), 6.72 (d, J=8.2 Hz, 1H), 6.66 (d, J=8.2 Hz, 1H), 5.36 (dd, J=6.3,1.8 Hz, 1H), 5.03 (s, 1H), 4.92-4.90 (m, 2H), 4.68 (d, J=6.3 Hz, 1H),3.46-3.10 (m, 8H), 3.00-2.71 (m, 5H), 2.69-2.51 (m, 4H), 2.43-2.35 (m,1H), 2.05 (d, J=18.6 Hz, 1H), 1.76 (d, J=12.6 Hz, 1H); ESI MS m/z 712[C₃₉H₄₁N₃O₁₀+H]⁺; HPLC (Method A) 98.9% (AUC), t_(R)=8.66 min.

Preparation of(S)-2-(((S)-4-(tert-Butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoyl)oxy)propanoicacid

A solution of (S)-1-tert-butyl 4-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)amino)succinate (3.42 g, 8.84 mmol), (S)-lacticacid (963 mg, 10.7 mmol), and 4-dimethylaminopyridine (104 mg, 0.85mmol) in tetrahydrofuran (40 mL) was treated with pyridine (0.85 mL,10.6 mmol) and heated at 50° C. under a nitrogen atmosphere for 16 h.After this time, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (100 mL) and washed with aqueous 10% citric acid (2×50 mL) andwater (50 mL). The organic layer was extracted with saturated aqueoussodium bicarbonate (2×50 mL). The combined aqueous bicarbonate layerswere acidified to pH ˜2 with 6 N hydrochloric acid and extracted withethyl acetate (4×50 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-2-(((S)-4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoyl)oxy)propanoicacid (1.47 mg, 46%) as a white semi-solid: ¹H NMR (300 MHz, CDCl₃) δ5.51-5.48 (m, 1H), 5.17 (q, J=7.2 Hz, 1H), 4.55-4.45 (br m, 1H),2.92-2.89 (m, 2H), 1.54 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), 1.44 (s, 9H),CO₂H proton not observed.

Preparation of (S)-1-tert-Butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate

A solution of(S)-2-(((S)-4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoyl)oxy)propanoicacid (1.47 g, 4.05 mmol) in tetrahydrofuran (20 mL) was treated withN-hydroxysuccinimide (513 mg, 4.46 mmol) andN,N′-dicyclohexylcarbodiimide (921 mg, 4.46 mmol) and stirred under anitrogen atmosphere for 4 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide (S)-1-tert-butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate (2.04 g, quantitative) as awhite foam: ¹H NMR (300 MHz, CDCl₃) δ 5.54-5.48 (m, 1H), 5.42 (q, J=7.2Hz, 1H), 4.51-4.45 (m, 1H), 3.08-2.82 (m, 6H), 1.68 (d, J=7.2 Hz, 3H),1.46 (s, 9H), 1.44 (s, 9H).

Preparation of(S)-4-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)1-tert-butyl 2-((tert-butoxycarbonyl)amino)succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled to −45° C. and treated dropwisewith a solution of (S)-1-tert-butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate (630 mg, 1.37 mmol) intetrahydrofuran (5 mL). After addition was complete, the mixture waswarmed to 0° C. After this time, the reaction mixture was treated withsaturated aqueous ammonium chloride (10 mL) and extracted with ethylacetate (2×25 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)-4-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)1-tert-butyl 2-((tert-butoxycarbonyl)amino)succinate (235 mg, 25%) as awhite solid: ESI MS m/z 745 [C₃₈H₅₂N₂O₁₃+H]⁺.

Preparation of(S)-2-Amino-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid bis(trifluoroacetic acid salt)

A solution of(S)-4-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)1-tert-butyl 2-((tert-butoxycarbonyl)amino)succinate (90 mg, 0.12 mmol)in methylene chloride (0.8 mL) was treated with trifluoroacetic acid(0.8 mL) and stirred under a nitrogen atmosphere at ambient temperaturefor 2 h. After this time, the reaction mixture was concentrated underreduced pressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 0-100% acetonitrile/water) and freezedried to provide(S)-2-amino-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid bis(trifluoroacetic acid salt) (30.2 mg, 41%) as a fluffy whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.33 (br s, 3H), 6.63 (apparent q,J=8.1 Hz, 2H), 5.58 (dd, J=6.0, 2.1 Hz, 1H), 5.01 (q, J=6.9 Hz, 1H),4.88 (s, 1H), 3.71 (m, 1H), 3.55 (m, 1H), 3.04-2.97 (m, 4H), 2.79-2.72(m, 4H), 2.63-2.40 (m, 2H), 2.28-2.22 (m, 1H), 2.04 (d, J=18.3 Hz, 1H),1.60 (d, J=12.6 Hz, 1H), 1.52 (d, J=6.9 Hz, 3H), CO₂H and two OH protonsnot observed; ESI MS m/z 489 [C₂₄H₂₈N₂O₉+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate)

A solution of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((tert-butoxycarbonyl)amino)propanoate) (233 mg, 0.307 mmol) inmethylene chloride (5 mL) was treated with trifluoroacetic acid (0.5mL), and the mixture was stirred at room temperature for 40 min. Afterthis time, LC-MS analysis of the reaction mixture showed cleavage of theBoc protecting groups. N,N-Diisopropylethylamine was added slowly untilthe reaction mixture tested basic by pH paper analysis (1.4 mL of baseadded). The mixture was treated with (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate (270 mg, 0.94 mmol) in oneportion and stirred at room temperature for 30 min. After this time, themixture was diluted with ethyl acetate and washed water and brine. Theorganic extracts were dried over sodium sulfate, filtered, andconcentrated. The residue was purified by reversed phase columnchromatography (50 g C18 column, 10-100% acetonitrile/water) to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate) (236 mg,84%): ESI MS m/z 902 [C₄₅H₆₇N₃O₁₄Si+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-Hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate)trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate) (235 mg,0.26 mmol) in tetrahydrofuran (5 mL) was treated with water (4 mL)followed by trifluoroacetic acid (3 mL), and the mixture was stirred atroom temperature for 2 h. After this time, the mixture was concentrated,and the residue was azeotroped with toluene to provide(S)-(4R,4aS,7aR,12bS)-9-Hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate)trifluoroacetic acid salt (240 mg, crude) that was used withoutpurification: ESI MS m/z 788 [C₃₉H₅₃N₃O₁₄+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-Hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-hydroxypropanamido)propanoate) trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)propanoate) (240 mg)in methylene chloride (5 mL) was treated with trifluoroacetic acid (0.5mL) and stirred at ambient temperature for 1 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas purified by reversed phase column chromatography (50 g C18 column,5-30% acetonitrile/water, with 0.1% trifluoroacetic acid) and freezedried to provide(S)-(4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((S)-2-hydroxypropanamido)propanoate) trifluoroacetic acid salt(81 mg, 39% over two steps) as a fluffy white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 9.70-9.40 (m, 1.6H), 7.92-7.84 (m, 2H), 6.73 (d, J=8.2 Hz,1H), 6.67 (d, J=8.2 Hz, 1H), 5.50 (dd, J=6.3, 1.6 Hz, 1H), 5.06 (s, 1H),4.73 (d, J=5.7 Hz, 1H), 4.01-3.91 (m, 2H), 3.45-3.13 (m, 10H), 3.17-2.89(m, 4H), 2.87-2.70 (m, 1H), 2.69-2.52 (m, 4H), 2.47-2.36 (m, 1H), 2.09(d, J=18.6 Hz, 1H), 1.78 (d, J=12.7 Hz, 1H), 1.21 (d, J=2.7 Hz, 3H),1.19 (d, J=2.7 Hz, 3H); ESI MS m/z 588 [C₂₉H₃₇N₃O₁₀+H]⁺; HPLC (MethodA) >99% (AUC), t_(R)=6.65 min.

Preparation of(S)—(S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobonzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-4-methylpentanoate

A solution of(S)—(S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-amino-4-methylpentanoate bis(trifluoroacetic acid salt) (83 mg, 0.12mmol) in tetrahydrofuran (2 mL) was treated with(S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)oxy)propanoate (22mg, 0.12 mmol) and N, N-diisopropylethylamine (30 mg, 0.039 mmol) at 0°C. and stirred under a nitrogen atmosphere for 1 h. After this time thereaction mixture was concentrated under reduced pressure. The residuewas purified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride) to provide(S)—(S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-4-methylpentanoate (54mg, 70%) as a white solid: ESI MS m/z 659 [C₃₄H₄₆N₂O₁₁+H]⁺.

Preparation of(S)—(S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-((S)-2-hydroxypropanamido)-4-methylpentanoate trifluoroacetic acidsalt

A solution of(S)—(S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-4-methylpentanoate (54mg, 0.082 mmol) in methylene chloride (1.0 mL) was treated withtrifluoroacetic acid (1.0 mL) and stirred under a nitrogen atmosphere atambient temperature for 2 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water) and freeze dried to provide(S)—(S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl2-((S)-2-hydroxypropanamido)-4-methylpentanoate trifluoroacetic acidsalt (19 mg, 32%) as a fluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ9.30 (s, 1H), 9.14 (br s, 1H), 7.89 (d, J=8.1 Hz, 1H), 6.66 (apparent q,J=8.1 Hz, 1H), 6.23 (s, 1H), 5.58 (dd, J=6.0, 2.1 Hz, 1H), 5.53 (br s,1H), 5.15 (q, J=6.9 Hz, 1H), 4.96 (s, 1H), 4.40 (m, 1H), 4.01 (m, 1H),3.62 (m, 1H), 3.11-3.03 (m, 2H), 2.84 (d, J=4.5 Hz, 3H), 2.65 (m, 1H),2.43 (m, 2H), 2.27 (m, 1H), 2.06 (d, J=17.7 Hz, 1H), 1.75-1.61 (m, 4H),1.53 (d, J=6.9 Hz, 3H), 1.21 (d, J=6.9 Hz, 3H), 0.91 (d, J=6.0 Hz, 3H),0.86 (d, J=5.7 Hz, 3H), one proton obscured by solvent peaks; ESI MS m/z559 [C₂₉H₃₈N₂O₉+H]⁺.

Preparation of (S)-1-tert-Butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)succinate

A mixture of (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-aminosuccinate trifluoroacetic acid salt (530 mg, 0.90 mmol) and(S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)oxy)propanoate (300mg, 1.05 mmol) in tetrahydrofuran (6 mL) was treated withN,N-diisopropylethylamine (0.60 mL, 3.4 mmol) and stirred at roomtemperature for 1 h. After this time, the mixture was diluted with ethylacetate and washed with water and brine. The organic extracts were driedover sodium sulfate, filtered, and concentrated. The residue waspurified by reversed phase column chromatography (50 g C18 column,5-100% acetonitrile/water) to provide (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)succinate (120 mg, 19%):ESI MS m/z 645 [C₃₃H₄₄N₂O₁₁+H]⁺.

Preparation of(S)-4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-((S)-2-hydroxypropanamido)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)succinate (312 mg, 0.484mmol) in methylene chloride (5 mL) was treated with trifluoroacetic acid(0.8 mL) and stirred at ambient temperature for 1 h. After this time,the reaction mixture was concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 3-20% acetonitrile/water, with 0.1% trifluoracetic acid) andfreeze dried to provide(S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-((S)-2-hydroxypropanamido)-4-oxobutanoicacid trifluoroacetic acid salt (29 mg, 10% over three steps) as a fluffywhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.99 (br s, 1H), 9.29 (s, 1H),9.16 (s, 1H), 8.05 (d, J=8.4 Hz, 1H), 6.67 (d, J=8.2 Hz, 1H), 6.63 (d,J=8.2 Hz, 1H), 6.23 (s, 1H), 5.69 (br s, 1H), 5.52-5.49 (m, 1H), 4.94(s, 1H), 4.72-4.64 (m, 1H), 4.02 (q, J=6.8 Hz, 1H), 3.61 (d, J=6.1 Hz,1H), 3.13-3.00 (m, 3H), 3.00-2.87 (m, 2H), 2.87-2.78 (m, 3H), 2.78-2.55(m, 1H), 2.48-2.38 (m, 1H), 2.27 (dd, J=17.8, 6.1 Hz, 1H), 2.05 (d,J=17.8 Hz, 1H), 1.62 (d, J=12.0 Hz, 1H), 1.22 (d, J=6.8 Hz, 1H), twoprotons obscured by solvent peaks; ESI MS m/z 489 [C₂₄H₂₈N₂O₉+H]⁺; HPLC(Method A) 94.8% (AUC), t_(R)=6.33 min.

Preparation of(S)-2-(2-((S)-2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoicacid

(S)-Lactic acid (399 mg, 4.43 mmol), (S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (1.00 g, 3.69 mmol),4-(dimethylamino)pyridine (45 mg, 0.37 mmol), pyridine (350 mg, 4.43mmol), and tetrahydrofuran (15 mL) were combined and heated at 50° C.under a nitrogen atmosphere for 48 h. After this time, the solvent wasremoved under reduced pressure, and the residue was partitioned betweenethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer wasseparated and washed with water (50 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide(S)-2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoicacid (810 mg, 89%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.19 (m,1H), 4.74 (m, 1H), 3.03 (td, J=17.1, 3.6 Hz, 1H), 2.88 (m, 1H),1.69-1.55 (m, 9H), CO₂H proton not observed.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate

A solution of(S)-2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoicacid (810 mg, 3.29 mmol) in tetrahydrofuran (12 mL) was treated withN-hydroxysuccinimide (417 mg, 3.62 mmol) andN,N′-dicyclohexylcarbodiimide (746 mg, 3.62 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (50 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-2,5-dioxopyrrolidin-1-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate (1.20g) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 5.49 (q, J=6.6 Hz, 1H),4.76 (m, 1H), 3.11 (m, 1H), 3.05 (q, J=3.0 Hz, 1H), 2.85 (s, 4H),1.73-1.57 (m, 9H).

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (425 mg, 1.06 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.3 mL, 1.3 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled to −45° C. and treated dropwisewith a solution of (S)-2,5-dioxopyrrolidin-1-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate (400mg, 1.17 mmol) in tetrahydrofuran (5 mL). After addition was complete,the mixture was warmed to 0° C. After this time, the reaction mixturewas treated with saturated aqueous ammonium chloride (10 mL) andextracted with ethyl acetate (2×25 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (40 g silica gelcolumn, 0-20% methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate (159mg, 23%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 6.90 (d, J=8.1 Hz,1H), 6.66 (d, J=8.4 Hz, 1H), 5.63 (m, 1H), 5.22 (m, 1H), 5.04 (d, J=9.9Hz, 1H), 4.75 (dd, J=6.9, 3.3 Hz, 1H), 3.19 (d, J=18.6 Hz, 1H), 3.06 (m,1H), 2.89 (m, 2H), 2.65 (dd, J=18.9, 6.3 Hz, 1H), 2.48-2.08 (m, 4H),2.39 (s, 3H), 1.62-1.51 (m, 20H), OH proton not observed.

Preparation of(S)-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-2-hydroxy-4-oxobutanoicacid hydrochloride

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(5-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate (159mg, 0.253 mmol) was treated with a 4.0 M solution of hydrochloric acidin 1,4-dioxane (5 mL, 20.0 mmol) and water (0.2 mL). The reactionmixture was stirred under a nitrogen atmosphere at ambient temperaturefor 2 h. After this time, the reaction mixture was concentrated underreduced pressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 0-100% acetonitrile/water) and freezedried to provide(S)-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-2-hydroxy-4-oxobutanoicacid hydrochloride (52.3 mg, 39%) as a fluffy white solid: ¹H NMR (300MHz, DMSO-d₆) δ 6.57 (apparent q, J=7.8 Hz, 2H), 5.56 (dd, J=5.7, 2.4Hz, 1H), 5.10 (q, J=6.9 Hz, 1H), 4.84 (s, 1H), 4.24 (dd, J=8.1, 4.2 Hz,1H), 3.14 (d, J=18.9 Hz, 1H), 3.01 (m, 1H), 2.79 (dd, J=15.6, 4.2 Hz,1H), 2.75-2.54 (m, 3H), 2.44 (s, 3H), 2.33-2.13 (m, 2H), 2.09-1.96 (m,2H), 1.50 (d, J=6.9 Hz, 3H), 1.42 (m, 1H), CO₂H, HCl, and OH protons notobserved; ESI MS m/z 490 [C₂₄H₂₇NO₁₀+H]⁺.

Preparation of(S)-2-(((S)-2-((tert-Butoxycarbonyl)oxy)propanoyl)oxy)-2-phenylaceticacid

A solution of (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)propanoate g, 6.96 mmol), mandelic acid(1.28 g, 8.41 mmol), and 4-dimethylaminopyridine (87 mg, 0.71 mmol) intetrahydrofuran (30 mL) was treated with pyridine (0.67 mL, 8.3 mmol)and heated at 50° C. under a nitrogen atmosphere for 20 h. After thistime, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (50 mL) and washed with aqueous 10% citric acid (2×25 mL) andwater (25 mL). The organic layer was extracted with saturated aqueoussodium bicarbonate (2×25 mL). The combined aqueous bicarbonate layerswere acidified to pH ˜2 with 6 N hydrochloric acid and extracted withethyl acetate (4×25 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)-2-phenylaceticacid (1.71 g, 76%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ7.48-7.36 (m, 5H), 6.00 (s, 1H), 5.06 (q, J=6.9 Hz, 1H), 1.62 (d, J=6.9Hz, 3H), 1.48 (s, 9H), CO₂H proton not observed; ESI MS m/z 647[(2×C₁₆H₂₀O₇)−H]⁻.

Preparation of(S)—(S)-2-((2,5-Dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl2-((tert-butoxycarbonyl)oxy)propanoate

A solution of(S)-2-(((S)-2-((tert-butoxycarbonyl)oxy)propanoyl)oxy)-2-phenylaceticacid (1.71 g, 5.27 mmol) in tetrahydrofuran (20 mL) was treated withN-hydroxysuccinimide (667 mg, 5.80 mmol) andN,N′-dicyclohexylcarbodiimide (1.21 g, 5.86 mmol) and stirred under anitrogen atmosphere for 2.5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide(S)—(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl2-((tert-butoxycarbonyl)oxy)propanoate (2.21 g, 99%) as an whitecrushable foam: ¹H NMR (300 MHz, CDCl₃) δ 7.55-7.51 (m, 2H), 7.47-7.42(m, 3H), 6.39 (s, 1H), 5.05 (q, J=7.2 Hz, 1H), 2.80 (s, 4H), 1.61 (d,J=7.2 Hz, 3H), 1.48 (s, 9H).

Preparation of(S)—(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-((tert-butoxycarbonyl)oxy)propanoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (800 mg, 1.99 mmol) in tetrahydrofuran (8 mL) was cooled to 0°C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (2.4 mL, 2.4 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 25 min andthen at ambient temperature for 25 min. The mixture was re-cooled to−78° C., and a solution of(S)—(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl2-((tert-butoxycarbonyl)oxy)propanoate (1.10 g, 2.59 mmol) intetrahydrofuran (10 mL) was added. The mixture was allowed to warm to 0°C. over 2 h. After this time, the mixture was treated with saturatedaqueous ammonium chloride (10 mL) and extracted with ethyl acetate (2×25mL). The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (40 g silica gel column, 0-20% methanol/methylenechloride, then 50 g C18 column, 10-100% acetonitrile/water) to provide(S)—(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-((tert-butoxycarbonyl)oxy)propanoate (685 mg, 56%) as a white solid:ESI MS m/z 708 [C₃₈H₄₅NO₁₂+H]⁺.

Preparation of(S)—(S)-2-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-hydroxypropanoate trifluoroacetic acid salt

A solution of(S)—(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-((tert-butoxycarbonyl)oxy)propanoate (100 mg, 0.141 mmol) in methylenechloride (2 mL) was treated with trifluoroacetic acid (2 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 2 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 0-100% acetonitrile/water) and freeze dried to provide(S)—(S)-2-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-hydroxypropanoate trifluoroacetic acid salt (52 mg, 59%) as a fluffywhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.13 (s, 1H),7.60-7.56 (m, 2H), 7.49-7.46 (m, 3H), 6.64 (apparent q, J=8.1 Hz, 2H),6.24 (s, 1H), 6.14 (s, 1H), 5.60-5.54 (m, 2H), 4.87 (s, 1H), 4.31 (m,1H), 3.03 (m, 1H), 2.82 (m, 3H), 2.64-2.39 (m, 3H), 2.30-2.22 (m, 1H),2.05 (d, J=18.0 Hz, 1H), 1.59 (d, J=11.4 Hz, 3H), 1.38 (d, J=6.9 Hz,3H); ESI MS m/z 508 [C₂₈H₂₉NO₈+H]⁺.

Preparation of (S)-2-Phenyl-2-(stearoyloxy)acetic acid

A solution of stearoyl chloride (364 mg, 1.20 mmol) in methylenechloride (5 mL) was cooled in an ice bath and treated with (S)-mandelicacid (182 mg, 1.20 mmol) and N,N-diisopropylethylamine (465 mg, 3.60mmol) and stirred under a nitrogen atmosphere for 16 h. After this time,10% aqueous citric acid (10 mL) was added, and the resulting mixture wasextracted with ethyl acetate (2×20 mL). The combined organics werewashed with brine (50 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography (40 g silica gel column, 0-100% ethyl acetate/heptane) toprovide of (S)-2-phenyl-2-(stearoyloxy)acetic acid (140 mg, 28%) as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.51-7.47 (m, 2H), 7.42-7.39(m, 3H), 5.97 (s, 1H), 2.45 (m, 2H), 1.68 (m, 3H), 1.27 (m, 28H), 0.88(t, J=6.6 Hz, 3H).

Preparation of (S)-2-((2,5-Dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethylstearate

A solution of (S)-2-phenyl-2-(stearoyloxy)acetic acid (140 mg, 0.334mmol) in tetrahydrofuran (3 mL) was treated with N-hydroxysuccinimide(42 mg, 0.368 mmol) and N,N′-dicyclohexylcarbodiimide (76 mg, 0.368mmol) and stirred under a nitrogen atmosphere for 5 h. After this time,the reaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether (100 mL), and thecombined filtrate and washings were concentrated under reduced pressure.The residue was triturated with diethyl ether to provide(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl stearate (191mg) as a white powder: ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.53 (m, 2H),7.46-7.43 (m, 3H), 6.34 (s, 1H), 2.81 (s, 4H), 2.46 (m, 2H), 1.68 (m,2H), 1.24 (m, 28H), 0.88 (t, J=6.6 Hz, 3H).

Preparation of(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethylstearate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (122 mg, 0.304 mmol) in tetrahydrofuran (5 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (0.37 mL, 0.37 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled to −45° C. and treated dropwisewith a solution of(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl stearate (172mg, 0.334 mmol) in tetrahydrofuran (2 mL). After addition was complete,the mixture was warmed to 0° C. After this time, the reaction mixturewas treated with saturated aqueous ammonium chloride (10 mL) andextracted with ethyl acetate (2×25 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (40 g, silicagel, 0-20% methanol/methylene chloride) to provide(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethylstearate (101 mg, 41%) as a white solid: ESI MS m/z 802 [C₄H₆₇NO₉+H]⁺.

Preparation of(S)-2-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethylstearate trifluoroacetic acid salt

A solution of(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethylstearate (100 mg, 0.126 mmol) in methylene chloride (0.8 mL) was treatedwith trifluoroacetic acid (0.8 mL) and stirred under a nitrogenatmosphere at ambient temperature for 1 h. After this time, the reactionmixture was concentrated under reduced pressure. The residue waspurified by reversed phase column chromatography (50 g C18 column,0-100% acetonitrile/water) and freeze dried to provide(S)-2-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethylstearate trifluoroacetic acid salt (37 mg, 34%) as a fluffy white solid:¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 9.13 (s, 1H), 7.58-7.55 (m,2H), 7.47-7.44 (m, 3H), 6.63 (q, J=8.1 Hz, 2H), 6.23 (s, 1H), 6.09 (s,1H), 5.58 (dd, J=6.3, 2.1 Hz, 1H), 4.86 (s, 1H), 3.06 (m, 1H), 2.82 (d,J=4.8 Hz, 3H), 2.64-2.22 (m, 6H), 2.05 (m, 1H), 2.58 (m, 3H), 1.23 (m,30H), 0.85 (t, J=6.9 Hz, 3H); ESI MS m/z 702 [C₄₃H₅₉NO₇+H]⁺; HPLC(Method A) 98.7% (AUC), t_(R)=16.14 min.

Preparation of(2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-amino-4-oxobutanoicacid) trifluoroacetic acid salt

A solution of (2S,2′S)-1-di-tert-butyl O′⁴,O⁴-((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(2-((tert-butoxycarbonyl)amino)succinate) (155 mg, 0.162 mmol) inmethylene chloride (6 mL) was treated with trifluoroacetic acid (0.6 mL)and stirred at ambient temperature for 18 h. After this time, thereaction mixture was concentrated under reduced pressure to obtain(2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-amino-4-oxobutanoicacid) trifluoroacetic acid salt (150 mg, quantitative) that was usedwithout purification: ESI MS m/z 646 [C₃₁H₄₃N₃O₁₀Si+H]⁺.

Preparation of(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-4-oxobutanoicacid)

A mixture of(2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-amino-4-oxobutanoicacid) trifluoroacetic acid salt (150 mg, 0.16 mmol) and(S)-2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)oxy)propanoate (105mg, 0.366 mmol) in methylene chloride (6 mL) was treated withN,N-diisopropylethylamine (0.20 mL, 1.2 mmol) and stirred at roomtemperature for 1 h. After this time, the reaction mixture was dilutedwith ethyl acetate and washed with water and brine. The organic extractswere dried over sodium sulfate, filtered, and concentrated to provide(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-4-oxobutanoicacid) (130 mg) that was used without purification: ESI MS m/z 990[C₄₇H₆₇N₃O₁₈Si+H]⁺.

Preparation of(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-((S)-2-hydroxypropanamido)-4-oxobutanoicacid) trifluoroacetic acid salt

A solution of(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-((S)-2-((tert-butoxycarbonyl)oxy)propanamido)-4-oxobutanoicacid) (130 mg) in methylene chloride (6 mL) was treated withtrifluoroacetic acid (2 mL) and stirred at ambient temperature for 30min. After this time, the reaction mixture was concentrated underreduced pressure to provide(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-((S)-2-hydroxypropanamido)-4-oxobutanoicacid) trifluoroacetic acid salt (130 mg) that was used withoutpurification: ESI MS m/z 790 [C₃₇H₅₁N₃O₁₄Si+H]⁺.

Preparation of(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-Hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-((S)-2-hydroxypropanamido)-4-oxobutanoicacid) trifluoroacetic acid salt

A solution of(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-((S)-2-hydroxypropanamido)-4-oxobutanoicacid) (130 mg) in tetrahydrofuran (4 mL) and water (3 mL) was treatedwith trifluoroacetic acid (3 mL) and stirred at room temperature for 1.5h. After this time, the mixture was concentrated. The residue waspurified by reversed phase column chromatography (50 g C18 column, 3-20%acetonitrile/water, with 0.1% trifluoracetic acid) and freeze dried toprovide(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-((S)-2-hydroxypropanamido)-4-oxobutanoicacid) trifluoroacetic acid salt (40 mg, 27% over three steps) as afluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.97 (br s, 1H), 9.40(br s, 2H), 8.10 (d, J=8.4 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 6.72 (d,J=8.2 Hz, 1H), 6.66 (d, J=8.2 Hz, 1H), 5.42 (dd, J=6.1, 1.7 Hz, 1H),5.01 (s, 1H), 4.76-4.60 (m, 3H), 4.06-3.98 (m, 2H), 2.30-3.10 (m, 4H),3.09-2.56 (m, 10H), 2.48-2.33 (m, 2H), 2.11 (d, J=19.0 Hz, 1H), 1.78 (d,J=12.8 Hz, 1H), 1.21 (d, J=6.8 Hz, 6H); ESI MS m/z 676 [C₃₁H₃₇N₃O₁₄+H]⁺.

Preparation of(S)-2-((S)-2-((tert-Butoxycarbonyl)oxy)-2-phenylacetoxy)propanoic acid

A solution of (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (2.00 g, 5.73 mmol), lacticacid (627 mg, 6.96 mmol), and 4-dimethylaminopyridine (68 mg, 0.56 mmol)in tetrahydrofuran (25 mL) was treated with pyridine (0.56 g, 7.0 mmol)and heated at 50° C. under a nitrogen atmosphere for 16 h. After thistime, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (50 mL) and washed with aqueous 10% citric acid (2×25 mL) andwater (25 mL). The organic layer was extracted with saturated aqueoussodium bicarbonate (2×25 mL). The combined aqueous bicarbonate layerswere acidified to pH ˜2 with 6 N hydrochloric acid and extracted withethyl acetate (4×25 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoic acid(1.42 g, 76%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.52-7.48(m, 2H), 7.40-7.37 (m, 3H), 5.85 (s, 1H), 5.23 (q, J=6.9 Hz, 1H),1.56-1.44 (m, 12H), CO₂H proton not observed; ESI MS m/z 647[(2×C₁₆H₂₀O₇)−H]⁻.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoate

A solution of(S)-2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoic acid(1.42 g, 4.36 mmol) in tetrahydrofuran (20 mL) was treated withN-hydroxysuccinimide (558 mg, 4.85 mmol) andN,N′-dicyclohexylcarbodiimide (997 mg, 4.83 mmol) and stirred under anitrogen atmosphere for 2.5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide(S)-2,5-dioxopyrrolidin-1-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoate (2.02 g,quantitative) as a white crushable foam: ¹H NMR (300 MHz, CDCl₃) δ7.51-7.45 (m, 2H), 7.40-7.34 (m, 3H), 5.85 (s, 1H), 5.53 (q, J=6.9 Hz,1H), 2.82 (br s, 4H), 1.69 (d, J=6.9 Hz, 3H), 1.51 (s, 9H).

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled to −45° C. and treated dropwisewith a solution of (S)-2,5-dioxopyrrolidin-1-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoate (577 mg,1.37 mmol) in tetrahydrofuran (2 mL). After addition was complete, themixture was warmed to 0° C. After this time, the reaction mixture wastreated with saturated aqueous ammonium chloride (10 mL) and extractedwith ethyl acetate (2×25 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by column chromatography (40 g silica gelcolumn, 0-20% methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoate (301 mg,34%) as a white solid: ESI MS m/z 708 [C₃₈H₄₅NO₁₂+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-hydroxy-2-phenylacetoxy)propanoate trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetoxy)propanoate (150 mg,0.212 mmol) in methylene chloride (2.0 mL) was treated withtrifluoroacetic acid (2.0 mL) and stirred under a nitrogen atmosphere atambient temperature for 2 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-hydroxy-2-phenylacetoxy)propanoate trifluoroacetic acid salt(49.6 mg, 37%) as a fluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.29(s, 1H), 9.14 (s, 1H), 7.46-7.43 (m, 2H), 7.38-7.27 (m, 3H), 6.64(apparent q, J=8.1 Hz, 2H), 6.21 (s, 1H), 6.16 (d, J=5.7 Hz, 1H), 5.49(dd, J=5.7, 2.1 Hz, 1H), 5.24-5.15 (m, 2H), 4.82 (s, 1H), 3.06 (m, 1H),2.83 (d, J=4.2 Hz, 3H), 2.63-2.22 (m, 6H), 2.03 (d, J=18.0 Hz, 1H), 1.60(d, J=10.2 Hz, 1H), 1.50 (d, J=6.9 Hz, 3H); ESI MS m/z 508[C₂₈H₂₉NO₈+H]⁺.

Preparation of tert-Butyl (2,5-dioxopyrrolidin-1-yl) succinate

A mixture of 4-(tert-butoxy)-4-oxobutanoic acid (9.75 g, 56.0 mmol) andN-hydroxysuccinimide (7.00 g, 60.8 mmol) in tetrahydrofuran (280 mL) at0° C. was treated with N,N′-dicyclohexylcarbodiimide (12.5 g, 60.8mmol). The ice bath was removed, and the reaction mixture was stirred atambient temperature for 4 h. After this time, diethyl ether (100 mL) wasadded, and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide tert-butyl (2,5-dioxopyrrolidin-1-yl)succinate (15.0 g) that was used without purification: ¹H NMR (300 MHz,CDCl₃) δ 2.91 (t, J=7.2 Hz, 2H), 2.83 (s, 4H), 2.66 (t, J=7.2 Hz, 2H),1.46 (s, 9H).

Preparation of (S)-2-((4-(tert-Butoxy)-4-oxobutanoyl)oxy)propanoic acid

A mixture of tert-butyl (2,5-dioxopyrrolidin-1-yl) succinate (7.60 g,28.0 mmol), (S)-2-hydroxypropanoic acid (3.00 g, 33.3 mmol), pyridine(2.7 mL, 33.5 mmol), and 4-dimethylaminopyridine (200 mg, 1.6 mmol) intetrahydrofuran (120 mL) was stirred at reflux for 24 h. After thistime, the mixture was cooled to room temperature, partially concentratedunder reduced pressure, diluted with ethyl acetate, and washed with 10%citric acid. The organic layer was extracted with saturated sodiumbicarbonate. The aqueous extract was carefully treated with 2 Nhydrochloric acid until acidic by pH paper analysis, and then extractedwith ethyl acetate. The organic extracts were dried over sodium sulfate,filtered, and concentrated to give(S)-2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic acid (4.84 g, 70%):ESI MS m/z 245 [C₁₁H₁₈O₆−H]⁻

Preparation of (S)-tert-Butyl(1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl) succinate

A mixture of (S)-2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic acid(4.80 g, 19.5 mmol) and N-hydroxysuccinimide (2.50 g, 21.7 mmol) intetrahydrofuran (100 mL) at 0° C. was treated withN,N′-dicyclohexylcarbodiimide (4.45 g, 21.6 mmol). The ice bath wasremoved, and the reaction mixture was stirred at ambient temperature for4 h. After this time, diethyl ether (100 mL) was added, and the mixturewas filtered. The filtrate was concentrated under reduced pressure toprovide (S)-tert-butyl(1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl) succinate (6.85 g)that was used without purification: ¹H NMR (300 MHz, CDCl₃) δ 5.44 (q,J=7.1 Hz, 1H), 2.84 (s, 4H), 2.72-2.52 (m, 4H), 1.68 (d, J=7.1 Hz, 3H),1.44 (s, 9H).

Preparation of(S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yltert-butyl succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.24 mmol) in tetrahydrofuran (10 mL) was cooled to−10° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.4 mL, 1.4 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to −10° C., and a solution of(S)-tert-butyl (1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)succinate (480 mg, 1.4 mmol) in tetrahydrofuran (5 mL) was added. Themixture was stirred at −10° C. to ambient temperature over 1 h. Afterthis time, the reaction mixture was cooled in an ice bath, treated withsaturated aqueous ammonium chloride, and extracted with ethyl acetate.The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by reversephase column chromatography (50 g C18 column, 5-100% acetonitrile/water)to provide(S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yltert-butyl succinate (420 mg, 53%): ESI MS m/z 630 [C₃₃H₄₃NO₁₁+H]⁺.

Preparation of4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yltert-butyl succinate (420 mg, 0.67 mmol) in methylene chloride (10 mL)was treated with trifluoroacetic acid (4 mL) and stirred at ambienttemperature for 2 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 5-25%acetonitrile/water) and freeze dried to provide4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (210 mg, 54%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 9.26 (br s, 1H), 6.66 (d, J=8.2 Hz, 1H), 6.60(d, J=8.2 Hz, 1H), 5.57 (dd, J=5.8, 2.0 Hz, 1H), 5.11 (q, J=7.0 Hz, 1H),4.92 (s, 1H), 3.02-2.78 (m, 2H), 2.8-2.58 (m, 5H), 2.50-2.31 (m, 1H),2.24 (dd, J=17.8, 5.4 Hz, 1H), 2.04 (d, J=19.9 Hz, 1H), 1.57 (d, J=11.3Hz, 1H), 1.51 (d, J=7.0 Hz, 3H), CO₂H and OH protons not observed, fiveprotons obscured by solvent peaks; ESI MS m/z 474 [C₂₄H₂₇NO₉+H]⁺; HPLC(Method A) 96.8% (AUC), t_(R)=7.36 min.

Preparation of (S)-2-((4-(tert-Butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid

A mixture of tert-butyl (2,5-dioxopyrrolidin-1-yl) succinate (7.60 g,28.0 mmol), (S)-2-hydroxy-2-phenylacetic acid (4.26 g, 28.0 mmol),pyridine (2.7 mL, 33.5 mmol), and 4-dimethylaminopyridine (200 mg, 1.6mmol) in tetrahydrofuran (120 mL) was stirred at reflux for 48 h. Afterthis time, the mixture was cooled to room temperature, partiallyconcentrated under reduced pressure, diluted with ethyl acetate, andwashed with 10% citric acid. The organic layer was extracted withsaturated sodium bicarbonate. The aqueous extract was carefully treatedwith 2 N hydrochloric acid until acidic by pH paper analysis, and thenextracted with ethyl acetate. The organic extracts were dried oversodium sulfate, filtered, and concentrated to give(S)-2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylacetic acid (6.00 g,70%): ¹H NMR (300 MHz, CDCl₃) 7.51-7.45 (m, 2H), 7.42-7.35 (m, 3H), 5.97(s, 1H), 2.76-2.69 (m, 2H), 2.63-2.55 (m, 2H), 1.41 (s, 9H), CO₂H protonnot observed.

Preparation of (S)-tert-Butyl(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl) succinate

A mixture of (S)-2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid (6.00 g, 19.5 mmol) and N-hydroxysuccinimide (2.50 g, 21.7 mmol) intetrahydrofuran (100 mL) at 0° C. was treated withN,N′-dicyclohexylcarbodiimide (4.45 g, 21.6 mmol). The ice bath wasremoved, and the reaction mixture was stirred at ambient temperature for4 h. After this time, diethyl ether (100 mL) was added, and the mixturewas filtered. The filtrate was concentrated under reduced pressure toprovide (S)-tert-butyl(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl) succinate (8.33g) that was used without purification: ¹H NMR (300 MHz, CDCl₃) δ7.57-7.51 (m, 2H), 7.46-7.40 (m, 3H), 6.35 (s, 1H), 2.80 (s, 4H),2.77-2.71 (m, 2H), 2.63-2.56 (m, 2H), 1.41 (s, 9H).

Preparation of(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyltert-butyl succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (505 mg, 1.26 mmol) in tetrahydrofuran (10 mL) was cooled to−10° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.4 mL, 1.4 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to −10° C., and (S)-tert-butyl(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl) succinate (670mg, 1.65 mmol) was added in one portion. The mixture was stirred at −10°C. to ambient temperature over 1 h. After this time, the reactionmixture was cooled in an ice bath, treated with saturated aqueousammonium chloride, and extracted with ethyl acetate. The combinedorganics were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by reversed phasecolumn chromatography (50 g C18 column, 5-100% acetonitrile/water) toprovide(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyltert-butyl succinate (420 mg, 48%): ESI MS m/z 692 [C₃₈H₄₅NO₁₁+H]⁺.

Preparation of4-((S)-2-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid trifluoracetic acid salt

A solution of(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyltert-butyl succinate (420 mg, 0.60 mmol) in methylene chloride (10 mL)was treated with trifluoroacetic acid (4 mL) and stirred at ambienttemperature for 2 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 5-30%acetonitrile/water) and freeze dried to provide4-((S)-2-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid trifluoracetic acid salt (210 mg, 54%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 7.59-7.51 (m, 2H), 7.50-7.40 (m, 3H), 6.57 (d.J=8.1 Hz, 1H), 6.51 (d, J=8.1 Hz, 1H), 6.07 (s, 1H), 5.55 (dd, J=5.5,2.6 Hz, 1H), 4.70 (s, 1H), 3.20-3.03 (m, 2H), 3.84 (d, J=6.0 Hz, 1H),2.74-2.63 (m, 2H), 2.62-2.54 (m, 3H), 2.43 (dd, J=10.9, 3.6 Hz, 1H),2.32 (s, 3H), 2.19 (dd, J=12.3, 4.5 Hz, 1H), 2.13-1.93 (m, 3H), 1.36 (d,J=10.8 Hz, 1H), CO₂H and OH protons not observed; ESI MS m/z 536[C₂₉H₂₉NO₉+H]⁺; HPLC (Method A) 96.7% (AUC), t_(R)=8.58 min.

Preparation of(2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-Hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-hydroxy-4-oxobutanoicacid)

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate) (93 mg, 0.13mmol) in 1,4-dioxane (2.5 mL) and water (0.1 mL) was treated with a 4 Nsolution of hydrogen chloride in 1,4-dioxane (0.4 mL, 1.6 mmol) andstirred at ambient temperature for 2.5 h. After this time, the reactionmixture was concentrated under reduced pressure. The residue waspurified by reversed phase column chromatography (50 g C18 column, 0-10%acetonitrile/water, with 0.1% trifluoracetic acid) and freeze dried toprovide(2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-hydroxy-4-oxobutanoicacid) (26 mg, 38%): ¹H NMR (300 MHz, DMSO-d₆) δ 9.44 (br s, 1H), 9.31(br s, 1H), 9.15 (br s, 1H), 6.75-6.58 (m, 3H), 5.46-5.41 (m, 2H), 5.02(s, 1H), 4.69 (d, J=5.9 Hz, 1H), 4.25-4.33 (m, 3H), 3.60-2.60 (m, 11H),2.47-2.37 (m, 1H), 2.10 (d, J=19.3 Hz, 1H), 1.77 (d, J=11.4 Hz, 1H); ESIMS m/z 534 [C₂₅H₂₇NO₁₂+H]⁺.

Preparation of(S)-2-(2-((S)-2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylaceticacid

(S)-Mandelic acid (935 mg, 6.15 mmol), (S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (2.00 g, 7.37 mmol),4-(dimethylamino)pyridine (75 mg, 0.62 mmol), pyridine (582 mg, 7.37mmol), and tetrahydrofuran (30 mL) were combined and heated at 50° C.under a nitrogen atmosphere for 48 h. After this time, the solvent wasremoved under reduced pressure, and the residue was partitioned betweenethyl acetate (30 mL) and 10% aqueous citric acid. The organic layer wasseparated and washed with water (50 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide(S)-2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylaceticacid (2.54 g, quantitative) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ7.50-7.32 (m, 5H), 6.01 (s, 1H), 4.77 (m, 1H), 3.14 (dd, J=17.1, 3.9 Hz,1H), 2.88 (m, 1H), 1.54 (m, 6H), CO₂H proton not observed.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate

A solution of(S)-2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylaceticacid (2.27 g, 7.37 mmol) in tetrahydrofuran (60 mL) was treated withN-hydroxysuccinimide (932 mg, 8.11 mmol) andN,N′-dicyclohexylcarbodiimide (1.67 g, 8.11 mmol) and stirred under anitrogen atmosphere for 4 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (50 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-2,5-dioxopyrrolidin-1-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate(3.52 g) as a yellow solid that was used without purification.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled to −45° C. and treated dropwisewith a solution of (S)-2,5-dioxopyrrolidin-1-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate(555 mg, 1.37 mmol) in tetrahydrofuran (5 mL). After addition wascomplete, the mixture was warmed to 0° C. After this time, the reactionmixture was treated with saturated aqueous ammonium chloride (10 mL) andextracted with ethyl acetate (2×25 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (40 g silica gelcolumn, 0-20% methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate(160 mg, 18%) as a white solid: ESI MS m/z 692 [C₃₇H₄₁NO₁₂+H]⁺.

Preparation of(S)-4-((S)-2-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-2-hydroxy-4-oxobutanoicacid hydrochloride

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate(160 mg, 0.231 mmol) was treated with a 4.0 M solution of hydrochloricacid in 1,4-dioxane (5 mL) and water (0.2 mL). The reaction mixture wasstirred under a nitrogen atmosphere at ambient temperature for 2 h.After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 0-100% acetonitrile/water) and freezedried to provide(S)-4-((S)-2-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-2-hydroxy-4-oxobutanoicacid hydrochloride (63.2 mg, 46%) as a fluffy white solid: ¹H NMR (300MHz, DMSO-d₆) δ 7.59-7.54 (m, 2H), 7.48-7.44 (m, 3H), 6.55 (apparent q,J=7.8 Hz, 2H), 6.08 (s, 1H), 5.56 (dd, J=5.7, 2.4 Hz, 1H), 4.74 (s, 1H),4.26 (dd, J=8.4, 4.2 Hz, 1H), 3.15 (s, 1H), 3.09 (s, 1H), 2.97 (d, J=5.7Hz, 1H), 2.88 (dd, J=15.9, 4.2 Hz, 1H), 2.73-1.95 (m, 6H), 2.41 (s, 3H),1.40 (d, J=11.1 Hz, 1H), CO₂H, HCl, and three OH protons not observed;ESI MS m/z 552 [C₂₉H₂₉NO₁₀+H]⁺.

Preparation of (S)-2-(Stearoyloxy)propanoic acid

A solution of stearic acid (5.02 g, 17.6 mmol) and benzotriazole (2.31g, 19.4 mmol) in tetrahydrofuran (80 mL) was treated withN,N′-dicyclohexylcarbodiimide (4.00 g, 19.4 mmol) and stirred under anitrogen atmosphere for 5.5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct, and the solidswere washed with diethyl ether. The combined filtrate and washings wereconcentrated. The residue was dissolved in tetrahydrofuran (90 mL) andcooled in an ice bath. The mixture was treated with lactic acid (1.61 g,17.9 mmol) and 4-dimethylaminopyridine (2.18 g, 17.8 mmol), and the icebath was removed. The mixture was stirred at ambient temperature under anitrogen atmosphere for 40 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate (250 mL) and washed with aqueous 10% citric acid (2×100 mL) andwater (100 mL). The organic layer was extracted with saturated aqueoussodium bicarbonate (2×100 mL). The combined aqueous bicarbonate layerswere acidified to pH ˜1 with 6 N hydrochloric acid and extracted withethyl acetate (2×100 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas dissolved/suspended in heptanes (100 mL), filtered to removeundissolved solids, washed with aqueous 10% citric acid (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide (S)-2-(stearoyloxy)propanoic acid (4.86 g, 77%) as acolorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.12 (q, J=7.2 Hz, 1H),2.41-2.32 (m, 2H), 1.67-1.52 (m, 5H), 1.31-1.27 (m, 28H), 0.88 (t, J=6.3Hz, 3H), CO₂H proton not observed.

Preparation of (S)-1-((2,5-Dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-ylstearate

A solution of (S)-2-(stearoyloxy)propanoic acid (4.85 g, 13.6 mmol) intetrahydrofuran (80 mL) was treated with N-hydroxysuccinimide (1.57 mg,13.6 mmol) and N,N′-dicyclohexylcarbodiimide (2.80 g, 13.6 mmol) andstirred under a nitrogen atmosphere for 1.5 h. After this time, thereaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether, and the combinedfiltrate and washings were concentrated under reduced pressure toprovide (S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl stearate(6.69 g, quantitative) as a white crushable foam: ¹H NMR (300 MHz,CDCl₃) δ 5.42 (q, J=7.2 Hz, 1H), 2.84 (br s, 4H), 2.42-2.37 (m, 2H),1.73-1.53 (m, 5H), 1.31-1.27 (m, 28H), 0.88 (t, J=6.3 Hz, 3H).

Preparation of(S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-ylstearate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled to −45° C. and treated dropwisewith a solution of(S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl stearate (621 mg,1.37 mmol) in tetrahydrofuran (5 mL). After addition was complete, themixture was warmed to 0° C. After this time, the reaction mixture wastreated with saturated aqueous ammonium chloride (20 mL) and extractedwith ethyl acetate (2×25 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by column chromatography (40 g silica gelcolumn, 0-20% methanol/methylene chloride) to provide(S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-ylstearate (600 mg, 25%) as a white solid: ESI MS m/z 740 [C₄₃H₆₅NO₉+H]⁺.

Preparation of(S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-ylstearate trifluoroacetic acid salt

A solution of(S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-ylstearate (300 mg, 0.405 mmol) in methylene chloride (3.0 mL) was treatedwith trifluoroacetic acid (3.0 mL) and stirred under a nitrogenatmosphere at ambient temperature for 1 h. After this time, the reactionmixture was concentrated under reduced pressure. The residue waspurified by reversed phase column chromatography (150 g C18 column,0-100% acetonitrile/water) and freeze dried to provide(S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-ylstearate trifluoroacetic acid salt (47.5 mg, 15%) as a fluffy whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.13 (s, 1H), 6.65(apparent q, J=8.1 Hz, 2H), 6.23 (s, 1H), 5.57 (dd, J=6.3, 2.1 Hz, 1H),5.09 (q, J=6.9 Hz, 1H), 4.95 (s, 1H), 3.09 (m, 1H), 2.84 (d, J=3.9 Hz,3H), 2.63-2.26 (m, 5H), 2.05 (d, J=18.0 Hz, 1H), 1.64-1.49 (m, 7H), 1.23(m, 30H), 0.85 (t, J=6.6 Hz, 3H); ESI MS m/z 640 [C₃₈H₅₇NO₇+H]⁺.

Preparation of (S,Z)-2-(Oleoyloxy)-2-phenylacetic acid

A solution of oleoyl chloride (2.13 g, 7.08 mmol) in methylene chloride(35 mL) was cooled in an ice bath and treated with (S)-mandelic acid(1.08 g, 7.08 mmol) and N,N-diisopropylethylamine (2.75 g, 21.2 mmol)and stirred under a nitrogen for 5 h. After this time, 10% aqueouscitric acid (100 mL) was added, and the resulting mixture was extractedwith ethyl acetate (2×100 mL). The combined organics were washed withbrine (100 mL), dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography (80 g silica gel column, 0-50% ethyl acetate/heptane) toprovide of (S,Z)-2-(oleoyloxy)-2-phenylacetic acid (1.26 g, 42%) as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.50-7.46 (m, 2H), 7.41-7.37(m, 3H), 5.95 (s, 1H), 5.36-5.32 (m, 2H), 2.47 (m, 2H), 1.99 (m, 4H),1.66 (m, 2H), 1.27 (m, 20H), 0.87 (t, J=6.6 Hz, 3H), CO₂H proton notobserved.

Preparation of (S)-2-((2,5-Dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyloleate

A solution of (S,Z)-2-(oleoyloxy)-2-phenylacetic acid (1.26 g, 3.02mmol) in tetrahydrofuran (30 mL) was treated with N-hydroxysuccinimide(383 mg, 3.33 mmol) and N,N′-dicyclohexylcarbodiimide (686 mg, 3.33mmol) and stirred under a nitrogen atmosphere for 5 h. After this time,the reaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether (100 mL), and thecombined filtrate and washings were concentrated under reduced pressure.The residue was triturated with diethyl ether to provide(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl oleate (1.68g) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.61-7.53 (m, 2H),7.46-7.42 (m, 3H), 6.34 (s, 1H), 5.36-5.32 (m, 2H), 2.87 (s, 4H), 2.45(m, 2H), 1.99 (m, 4H), 1.66 (m, 2H), 1.27 (m, 20H), 0.88 (t, J=6.6 Hz,3H).

Preparation of(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyloleate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl oleate (703mg, 1.37 mmol) in tetrahydrofuran (5 mL). After addition was complete,the mixture was warmed to 0° C. After this time, the reaction mixturewas treated with saturated aqueous ammonium chloride (20 mL) andextracted with ethyl acetate (2×50 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (40 g, silicagel, 0-20% methanol/methylene chloride) to provide(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyloleate (900 mg, 90%) as a white solid: ESI MS m/z 800 [C₄₈H₆₅NO₉+H]⁺.

Preparation of(S)-2-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyloleate trifluoroacetic acid salt

A solution of(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyloleate (450 mg, 0.625 mmol) in methylene chloride (3.0 mL) was treatedwith trifluoroacetic acid (3.0 mL) and stirred under a nitrogenatmosphere at ambient temperature for 2 h. After this time, the reactionmixture was concentrated under reduced pressure. The residue waspurified by reversed phase column chromatography (150 g C18 column,0-100% acetonitrile/water) and freeze dried to provide(S)-2-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyloleate trifluoroacetic acid salt (31 mg, 6%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 9.12 (s, 1H), 7.58-7.54 (m, 2H),7.48-7.45 (m, 3H), 6.64 (q, J=8.1 Hz, 2H), 6.23 (s, 1H), 6.09 (s, 1H),5.58 (dd, J=6.3, 2.1 Hz, 1H), 5.32 (t, J=4.8 Hz, 2H), 4.86 (s, 1H), 3.04(m, 1H), 2.82 (d, J=4.8 Hz, 3H), 2.64-2.22 (m, 3H), 2.08-1.96 (m, 5H),1.60-1.40 (m, 4H), 1.23 (m, 24H), 0.85 (t, J=6.9 Hz, 3H); ESI MS m/z 700[C₄₃H₅₇NO₇+H]⁺; HPLC (Method A) 95.1% (AUC), t_(R)=15.51 min.

Preparation of (S)-4-tert-Butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)oxy)succinate

A mixture of(S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoic acid(2.70 g, 9.31 mmol) and N-hydroxysuccinimide (1.25 g, 10.9 mmol) intetrahydrofuran (50 mL) at 0° C. was treated withN,N′-dicyclohexylcarbodiimide (2.20 g, 10.7 mmol). The ice bath wasremoved, and the reaction mixture was stirred at ambient temperature for4 h. After this time, diethyl ether (100 mL) was added, and the mixturewas filtered. The filtrate was concentrated under reduced pressure toprovide (S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)oxy)succinate (3.78 g) that was used withoutpurification: ¹H NMR (300 MHz, CDCl₃) δ 5.61 (dd, J=8.0, 4.8 Hz, 1H),2.98-2.93 (m, 2H), 2.84 (s, 4H), 1.51 (s, 9H), 1.47 (s, 9H).

Preparation of(S)-2-((S)-4-(tert-Butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoyl)oxy)propanoicacid

A mixture of (S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)oxy)succinate (3.38 g, 8.73 mmol),(S)-2-hydroxypropanoic acid (1.20 g, 13.3 mmol), pyridine (1.1 mL, 14mmol), and 4-dimethylaminopyridine (100 mg, 0.8 mmol) in tetrahydrofuran(40 mL) was stirred at reflux for 18 h. After this time, the mixture wascooled to room temperature, partially concentrated under reducedpressure, diluted with ethyl acetate, and washed with 10% citric acid.The organic layer was extracted with saturated sodium bicarbonate. Theaqueous extract was carefully treated with 2 N hydrochloric acid untilacidic by pH paper analysis, and then extracted with ethyl acetate. Theorganic extracts were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to give(S)-2-(((S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoyl)oxy)propanoicacid (1.58 g, 50%): ¹H NMR (300 MHz, CDCl₃) δ 5.37-5.22 (m, 2H),2.96-2.82 (m, 2H), 1.57 (d, J=7.1 Hz, 3H), 1.49 (s, 9H), 1.46 (s, 9H),CO₂H proton not observed.

Preparation of (S)-4-tert-Butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate

A mixture of(S)-2-(((S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoyl)oxy)propanoicacid (1.58 g, 4.36 mmol) and N-hydroxysuccinimide (550 mg, 4.78 mmol) intetrahydrofuran (30 mL) at 0° C. was treated withN,N′-dicyclohexylcarbodiimide (990 mg, 4.80 mmol). The ice bath wasremoved, and the reaction mixture was stirred at ambient temperature for4 h. After this time, diethyl ether (30 mL) was added, and the mixturewas filtered. The filtrate was concentrated under reduced pressure toprovide (S)-4-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate (2.2 g) that was used withoutpurification: ¹H NMR (300 MHz, CDCl₃) δ 5.56 (q, J=7.1 Hz, 1H), 3.37(dd, J=8.8, 3.9 Hz, 1H), 2.98-2.93 (m, 2H), 2.84 (s, 4H), 1.72 (d, J=7.1Hz, 3H), 1.50 (s, 9H), 1.46 (s, 9H).

Preparation of(S)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)4-tert-butyl 2-((tert-butoxycarbonyl)oxy)succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (700 mg, 1.74 mmol) in tetrahydrofuran (15 mL) was cooled to0° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.95 mL, 1.95 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 25 min andthen at ambient temperature for 25 min. The mixture was re-cooled to−78° C., and (S)-4-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate (900 mg, 1.96 mmol) was added. Themixture was allowed to warm to 0° C. over 2 h. After this time, themixture was treated with saturated aqueous ammonium chloride, andextracted with ethyl acetate. The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (150 g C18column, 5-100% acetonitrile/water) to provide(S)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)4-tert-butyl 2-((tert-butoxycarbonyl)oxy)succinate (260 mg, 20%): ESI MSm/z 746 [C₃₈H₅₁NO₁₄+H]⁺.

Preparation of(S)-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(S)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)4-tert-butyl 2-((tert-butoxycarbonyl)oxy)succinate (260 mg, 0.35 mmol)in methylene chloride (6 mL) was treated with trifluoroacetic acid (3mL) and stirred at ambient temperature for 1.5 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas purified by reversed phase column chromatography (50 g C18 column,3-20% acetonitrile/water, with 0.1% trifluoracetic acid) and freezedried to provide(S)-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt (89 mg, 39%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 12.39 (br s, 1H), 9.30 (s, 1H), 9.17 (s, 1H),6.69 (d, J=8.1 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 6.28 (s, 1H), 5.84 (brs, 1H), 5.59 (dd, J=5.9, 2.0 Hz, 1H), 5.17 (q, J=7.0 Hz, 1H), 4.97 (s,1H), 4.47 (dd, J=8.6, 4.0 Hz, 1H), 3.63 (d, J=6.2 Hz, 1H), 3.13-3.00 (m,2H), 2.84 (d, J=3.3 Hz, 3H), 2.72 (dd, J=16.0, 4.2 Hz, 1H), 2.69-2.57(m, 1H), 2.50-2.40 (m, 1H), 2.29 (dd, J=18.0, 6.0 Hz, 1H), 2.06 (d,J=18.0 Hz, 1H), 1.62 (d, J=11.2 Hz, 1H), 1.53 (d, J=7.0 Hz, 3H), twoprotons obscured by solvent peaks; ESI MS m/z 490 [C₂₄H₂₇NO₁₀+H]⁺; HPLC(Method A) 97.9% (AUC), t_(R)=6.68 min.

Preparation of (S)-2-(((S)-2-(Stearoyloxy)propanoyl)oxy)propanoic acid

(S)-Lactic acid (238 mg, 2.65 mmol),(S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl stearate (1.00 g,2.20 mmol), 4-(dimethylamino)pyridine (27 mg, 0.220 mmol), pyridine (210mg, 7.65 mmol), and tetrahydrofuran (10 mL) were combined and heated at60° C. under a nitrogen atmosphere for 24 h. After this time, thesolvent was removed under reduced pressure, and the residue wasparticipated between ethyl acetate (30 mL) and 10% aqueous citric acid.The organic layer was separated and washed with water (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide (S)-2-(((S)-2-(stearoyloxy)propanoyl)oxy)propanoic acid (608mg, 64%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 5.22 (dd, J=14.4,7.2 Hz, 1H), 5.11 (dd, J=14.4, 7.2 Hz, 1H), 2.38 (m, 2H), 1.58-1.54 (m,6H), 1.28 (m, 30H), 0.86 (t, J=11.4 Hz, 3H), CO₂H proton not observed.

Preparation of(S)-1-(((S)-1-((2,5-Dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-ylstearate

A solution of (S)-2-(((S)-2-(stearoyloxy)propanoyl)oxy)propanoic acid(608 mg, 1.42 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (179 mg, 1.56 mmol) andN,N′-dicyclohexylcarbodiimide (321 mg, 1.56 mmol) and stirred at roomtemperature under a nitrogen atmosphere for 4 h. After this time, thereaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether (50 mL), and thecombined filtrate and washings were concentrated under reduced pressure.The residue was triturated with diethyl ether to provide(S)-1-(((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-ylstearate (803 mg) as a white solid that was used without purification.

Preparation of(S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-ylstearate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (208 mg, 0.519 mmol) in tetrahydrofuran (5 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (0.62 mL, 0.62 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-1-(((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-ylstearate (300 mg, 0.571 mmol) in tetrahydrofuran (2.5 mL). Afteraddition was complete, the mixture was warmed to 0° C. After this time,the reaction mixture was treated with saturated aqueous ammoniumchloride (10 mL) and extracted with ethyl acetate (2×25 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (40 g silica gel column, 0-20% methanol/methylenechloride) to provide(S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-ylstearate (320 mg, 75%) as a white solid: ESI MS m/z 812 [C₄₆H₆₉NO₁₁+H]⁺.

Preparation of(S)-1-((S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-ylstearate trifluoroacetic acid salt

A solution of(S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-ylstearate (320 mg, 0.394 mmol) in methylene chloride (3 mL) was treatedwith trifluoroacetic acid (3 mL) and stirred under a nitrogen atmosphereat ambient temperature for 2 h. After this time, the reaction mixturewas concentrated under reduced pressure. The residue was purified byreversed phase column chromatography (150 g C18 column, 0-100%acetonitrile/water) and freeze dried to provide(S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-ylstearate trifluoroacetic acid salt (70.3 mg, 20%) as a fluffy whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.13 (s, 1H), 6.65(apparent q, J=8.1 Hz, 2H), 6.23 (s, 1H), 5.58 (dd, J=6.3, 2.1 Hz, 1H),5.23 (q, J=6.9 Hz, 1H), 5.08 (q, J=7.2 Hz, 1H), 4.95 (s, 1H), 3.06 (m,1H), 2.83 (d, J=4.8 Hz, 3H), 2.63-2.25 (m, 5H), 2.06 (d, J=17.4 Hz, 1H),1.64-1.46 (m, 10H), 1.23 (m, 30H), 0.85 (t, J=6.9 Hz, 3H); ESI MS m/z712 [C₄₁H₆₁NO₉+H]⁺.

Preparation of (S,Z)-2-(Oleoyloxy)propanoic acid

A solution of oleic acid (5.04 g, 17.9 mmol) and1H-benzo[d][1,2,3]triazole (2.35 g, 19.8 mmol) in tetrahydrofuran (80mL) was treated with N,N′-dicyclohexylcarbodiimide (4.13 g, 20.0 mmol)and stirred under a nitrogen atmosphere for 16 h. After this time, thereaction mixture was filtered to remove the solid dicyclohexylureabyproduct, and the solids were washed with diethyl ether. The combinedfiltrate and washings were concentrated. The residue was dissolved intetrahydrofuran (75 mL) and cooled in an ice bath. The mixture wastreated with (S)-lactic acid (1.62 g, 18.0 mmol) and4-dimethylaminopyridine (2.20 g, 18.0 mmol), and the ice bath wasremoved. The mixture was stirred at ambient temperature under a nitrogenatmosphere for 40 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate (250 mL) and washed with aqueous 10% citric acid (2×100 mL),water (100 mL), and brine (100 mL). The organic layer was extracted withsaturated aqueous sodium bicarbonate (2×100 mL). The combined aqueousbicarbonate layers were acidified to pH ˜1 with 6 N hydrochloric acidand extracted with ethyl acetate (2×100 mL). The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was dissolved/suspended in heptanes (100 mL),washed with aqueous 10% citric acid (50 mL) and brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide (S,Z)-2-(oleoyloxy)propanoic acid (4.50 g, 71%) as acolorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.36-5.30 (m, 2H), 5.10 (q,J=5.4 Hz, 1H), 2.41-2.32 (m, 2H), 2.02-1.98 (m, 4H), 1.67-1.52 (m, 5H),1.31-1.27 (m, 20H), 0.88 (t, J=6.3 Hz, 3H), CO₂H proton not observed.

Preparation of (S)-1-((2,5-Dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yloleate

A solution of (S,Z)-2-(oleoyloxy)propanoic acid (4.50 g, 12.7 mmol) intetrahydrofuran (60 mL) was treated with N-hydroxysuccinimide (1.58 mg,13.8 mmol) and N,N′-dicyclohexylcarbodiimide (2.91 g, 14.1 mmol) andstirred under a nitrogen atmosphere for 1.5 h. After this time, thereaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether, and the combinedfiltrate and washings were concentrated under reduced pressure toprovide (S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl oleate(6.20 g, quantitative) as an amber semi-solid: ¹H NMR (300 MHz, CDCl₃) δ5.42 (q, J=7.2 Hz, 1H), 5.36-5.32 (m, 2H), 2.84 (br s, 4H), 2.42-2.37(m, 2H), 2.02-1.98 (m, 4H), 1.72-1.53 (m, 5H), 1.30-1.27 (m, 20H), 0.88(t, J=6.3 Hz, 3H).

Preparation of(S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yloleate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (640 mg, 1.59 mmol) in tetrahydrofuran (10 mL) was cooled to0° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.75 mL, 1.75 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 25 min andthen at ambient temperature for 25 min. The mixture was re-cooled to−78° C., and a solution of(S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl oleate (830 mg,1.83 mmol) in tetrahydrofuran (5 mL) was added. The mixture was allowedto warm to 0° C. over 2 h. After this time, the mixture was treated withsaturated aqueous ammonium chloride (10 mL) and extracted with ethylacetate (2×25 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride) to provide(S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yloleate (820 mg, 69%) as a yellow solid: ESI MS m/z 738 [C₄₃H₆₃NO₉+H]⁺.

Preparation of(S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yloleate trifluoroacetic acid salt

A solution of(S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yloleate (410 mg, 0.556 mmol) in methylene chloride (3 mL) was treatedwith trifluoroacetic acid (3 mL) and stirred under a nitrogen atmosphereat ambient temperature for 1 h. After this time, the reaction mixturewas concentrated under reduced pressure. The residue was purified byreversed phase column chromatography (150 g C18 column, 0-100%acetonitrile/water) and freeze dried to provide(S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yloleate trifluoroacetic acid salt (121 mg, 28%) as a fluffy white solid:¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.14 (s, 1H), 6.65 (apparentq, J=8.1 Hz, 2H), 6.23 (s, 1H), 5.57 (dd, J=5.7, 2.1 Hz, 1H), 5.32 (t,J=4.5 Hz, 2H), 5.09 (q, J=7.2 Hz, 1H), 4.95 (s, 1H), 3.09 (m, 1H), 2.83(d, J=4.5 Hz, 3H), 2.67-2.24 (m, 7H), 2.09-1.95 (m, 5H), 1.64-1.49 (m,6H), 1.25 (m, 21H), 0.85 (t, J=6.3 Hz, 3H); ESI MS m/z 638[C₃₈H₅₅NO₇+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((tert-butoxycarbonyl)amino)propanoate and(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((tert-butoxycarbonyl)amino)propanoate)

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (1.00 g, 2.49 mmol) in tetrahydrofuran (15 mL) was cooled to0° C. and treated dropwise with a 3.1 M solution of lithium tert-amylatein heptanes (0.90 mL, 2.80 mmol). After addition was complete, themixture was stirred at 0° C. for 25 min and then at ambient temperaturefor 25 min. The mixture was re-cooled to −78° C., and2,5-dioxopyrrolidin-1-yl 3-((tert-butoxycarbonyl)amino)propanoate (900mg, 3.32 mmol) was added. The mixture was allowed to warm to 0° C. over2 h. After this time, the mixture was treated with saturated aqueousammonium chloride and extracted with ethyl acetate. The combinedorganics were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by reversed phasecolumn chromatography (150 g C18 column, 5-100% acetonitrile/water) toprovide(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((tert-butoxycarbonyl)amino)propanoate (520 mg, 36%): ESI MS m/z 573[C₃₀H₄₀N₂O₉+H]⁺ and(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((tert-butoxycarbonyl)amino)propanoate): ESI MS m/z 744[C₃₈H₅₃N₃O₁₂+H]⁺.

Preparation of(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-aminopropanoate trifluoroacetic acid salt

A solution of(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-((tert-butoxycarbonyl)amino)propanoate (520 mg, 0.91 mmol) inmethylene chloride (8 mL) was treated with trifluoroacetic acid (4 mL),and the mixture was stirred at room temperature for 1 h. After thistime, the reaction mixture was concentrated to provide(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-aminopropanoate trifluoroacetic acid salt (500 mg, crude) that waswithout purification: ESI MS m/z 373 [C₂₀H₂₄N₂O₅+H]⁺.

Preparation of (S)-tert-Butyl3-((tert-butoxycarbonyl)oxy)-4-((3-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)amino)-4-oxobutanoate

A mixture of(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl3-aminopropanoate trifluoroacetic acid salt (500 mg, 0.83 mmol) and(S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)oxy)succinate (390 mg, 1.01 mmol) intetrahydrofuran (5 mL) at 0° C. was treated withN,N-diisopropylethylamine (0.4 mL) and stirred for 1.5 h. After thistime, the mixture was diluted with ethyl acetate and washed with waterand brine. The organic extracts were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography (50 g C18 column, 5-100%acetonitrile/water) to provide (S)-tert-butyl3-((tert-butoxycarbonyl)oxy)-4-((3-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)amino)-4-oxobutanoate(240 mg, 41% over two steps): ESI MS m/z 645 [C₃₃H₄₄N₂O₁₁+H]⁺.

Preparation of(S)-4-((3-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)amino)-3-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt

A solution of (S)-tert-butyl3-((tert-butoxycarbonyl)oxy)-4-((3-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)amino)-4-oxobutanoate(240 mg, 0.37 mmol) in methylene chloride (6 mL) was treated withtrifluoroacetic acid (3 mL) and stirred at ambient temperature for 1 h.After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 3-20% acetonitrile/water, with 0.1%trifluoracetic acid) and freeze dried to provide(S)-4-((3-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)amino)-3-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt (118 mg, 53%): ¹H NMR (300 MHz, DMSO-d₆)δ 12.23 (br s, 1H), 9.30 (s, 1H), 9.15 (s, 1H), 7.97 (t, J=6.0 Hz, 1H),6.64 (apparent q, J=8.1 Hz, 2H), 6.22 (s, 1H), 5.85 (s, 1H), 5.55 (dd,J=6.0, 2.1 Hz, 1H), 4.96 (s, 1H), 4.22 (dd, J=8.7, 3.6 Hz, 1H),3.62-3.43 (m, 5H), 3.11-3.02 (m, 1H), 2.84 (d, J=4.8 Hz, 3H), 2.66-2.60(m, 4H), 2.49-2.23 (m, 3H), 2.05 (d, J=17.7 Hz, 1H), 1.62 (d, J=10.5 Hz,1H); ESI MS m/z 508 [C₂₄H₂₈N₂O₉+H]⁺.

Preparation of(E)-4-((3-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)amino)-4-oxobut-2-enoicacid trifluoroacetic acid salt

(E)-4-((3-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)amino)-4-oxobut-2-enoicacid trifluoroacetic acid salt (10 mg, 4%) was isolated as a byproductfrom the deprotection step of (S)-tert-butyl3-((tert-butoxycarbonyl)oxy)-4-((3-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-oxopropyl)amino)-4-oxobutanoatewith trifluoroacetic acid in methylene chloride: ¹H NMR (300 MHz,DMSO-d₆) δ 12.86 (br s, 1H), 9.30 (s, 1H), 9.15 (s, 1H), 8.65 (t, J=5.5Hz, 1H), 6.92 (d, J=15.5 Hz, 1H), 6.68 (d, J=8.1 Hz, 1H), 6.62 (d, J=8.1Hz, 1H), 6.53 (d, J=15.5 Hz, 1H), 6.21 (s, 1H), 5.55 (dd, J=6.0, 2.0 Hz,1H), 4.96 (s, 1H), 3.61 (d, J=6.3 Hz, 1H), 3.50-3.42 (m, 2H), 3.13-3.01(m, 3H), 2.84 (d, J=4.7 Hz, 3H), 2.70-2.62 (m, 3H), 2.50-2.40 (m, 1H),2.32-2.22 (m, 1H), 2.06 (d, J=17.5 Hz, 1H), 1.62 (d, J=11.3 Hz, 1H); ESIMS m/z 471 [C₂₄H₂₆N₂O₈+H]⁺; HPLC (Method A) 98.9% (AUC), t_(R)=6.64 min.

Preparation of (S)-4-(tert-Butoxy)-2-hydroxy-4-oxobutanoic acid

A solution of (S)-tert-butyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (4.58 g, 19.9 mmol) inacetic acid (31.5 mL) and water (13.5, mL) was stirred at 60° C. for 4h. After this time, the solvent was removed under reduced pressure. Theresidue was dried under vacuum to provide(S)-4-(tert-butoxy)-2-hydroxy-4-oxobutanoic acid (3.37 g, 89%) as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 4.48 (t, J=5.7 Hz, 1H), 3.72(br s, 1H), 2.83 (m, 2H), 1.48 (m, 9H), CO₂H proton not observed.

Preparation of (Z)-1-(1H-Benzo[d][1,2,3]triazol-1-yl)octadec-9-en-1-one

A solution of oleic acid (2.00 g, 7.08 mmol) in tetrahydrofuran (30 mL)was treated with 1H-benzo[d][1,2,3]triazole (928 mg, 7.79 mmol) andN,N′-dicyclohexylcarbodiimide (1.61 g, 7.79 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide(Z)-1-(1H-benzo[d][1,2,3]triazol-1-yl)octadec-9-en-1-one (3.13 g) as awhite solid that was used without purification.

Preparation of (S,Z)-4-(tert-Butoxy)-2-(oleoyloxy)-4-oxobutanoic acid

(S)-4-(tert-Butoxy)-2-hydroxy-4-oxobutanoic acid (992 mg, 5.22 mmol),(Z)-1-(1H-benzo[d][1,2,3]triazol-1-yl)octadec-9-en-1-one (2.00 g, 5.22mmol), 4-(dimethylamino)pyridine (638 mg, 5.22 mmol), andtetrahydrofuran (40 mL) were combined and stirred at room temperatureunder a nitrogen atmosphere for 48 h. After this time, the solvent wasremoved under reduced pressure, and the residue was partitioned betweenethyl acetate (30 mL) and 10% aqueous citric acid. The organic layer wasseparated and washed with water (50 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (40 g silica gel column, 0-50% ethylacetate/heptane) to provide(S,Z)-4-(tert-butoxy)-2-(oleoyloxy)-4-oxobutanoic acid (850 mg, 36%) asa colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.47 (t, J=5.7 Hz, 1H),5.36-5.32 (m, 2H), 2.84 (d, J=0.9 Hz, 2H), 2.38 (m, 2H), 2.00 (m, 4H),1.64 (m, 2H), 1.45 (s, 9H), 1.35-1.27 (m, 20H), 0.85 (m, 3H), CO₂Hproton not observed.

Preparation of (S,Z)-4-tert-Butyl 1-(2,5-dioxopyrrolidin-1-yl)2-(oleoyloxy)succinate

A solution of (S,Z)-4-(tert-butoxy)-2-(oleoyloxy)-4-oxobutanoic acid(820 mg, 1.80 mmol) in tetrahydrofuran (20 mL) was treated withN-hydroxysuccinimide (228 mg, 1.98 mmol) andN,N′-dicyclohexylcarbodiimide (408 mg, 1.98 mmol) and stirred under anitrogen atmosphere for 4 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S,Z)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-(oleoyloxy)succinate (1.06 g) as a whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 5.76 (dd, J=8.1, 1.8 Hz, 1H), 5.36-5.32(m, 2H), 2.97 (m, 2H), 2.84 (s, 4H), 2.38 (m, 2H), 2.00 (m, 4H), 2.48(m, 2H), 1.44 (s, 9H), 1.29-1.27 (m, 20H), 0.88 (t, J=6.3 Hz, 3H).

Preparation of(S)-1-((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-((Z)-2-oxononadec-10-en-1-yl)succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (328 mg, 0.818 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (0.98 mL, 0.98 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S,Z)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl) 2-(oleoyloxy)succinate(496 mg, 0.900 mmol) in tetrahydrofuran (5 mL). After addition wascomplete, the mixture was warmed to 0° C. After this time, the reactionmixture was treated with saturated aqueous ammonium chloride (20 mL) andextracted with ethyl acetate (2×50 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (40 g silica gelcolumn, 0-20% methanol/methylene chloride) to provide(S)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-((Z)-2-oxononadec-10-en-1-yl)succinate (548 mg, 80%) as awhite solid: ESI MS m/z 838 [C₄₆H₇₁NO₁₁+H]⁺.

Preparation of(S,Z)-3-((((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)carbonyl)-5-oxodocos-13-enoicacid trifluoroacetic acid salt

A solution of(S)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-((Z)-2-oxononadec-10-en-1-yl)succinate (270 mg, 0.396mmol) in methylene chloride (3 mL) was treated with trifluoroacetic acid(3 mL) and stirred under a nitrogen atmosphere at ambient temperaturefor 1 h. After this time, the reaction mixture was concentrated underreduced pressure. The residue was purified by reversed phase columnchromatography (150 g C18 column, 0-100% acetonitrile/water) and freezedried to provide(S,Z)-3-((((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)carbonyl)-5-oxodocos-13-enoicacid trifluoroacetic acid salt (52.2 mg, 16%) as a fluffy white solid:¹H NMR (300 MHz, DMSO-d₆) δ 12.75 (br s, 1H), 9.26 (s, 1H), 9.13 (s,1H), 6.64 (apparent q, J=8.1 Hz, 2H), 6.23 (s, 1H), 5.59 (dd, J=6.0, 2.1Hz, 1H), 5.40 (dd, J=7.8, 4.2 Hz, 1H), 5.32 (t, J=4.5 Hz, 2H), 4.93 (s,1H), 3.62-3.41 (m, 1H), 3.04-2.88 (m, 4H), 2.84 (d, J=4.5 Hz, 3H),2.66-2.24 (m, 6H), 2.09-1.97 (m, 4H), 1.64-1.52 (m, 3H), 1.25 (m, 23H),0.85 (t, J=6.9 Hz, 3H); ESI MS m/z 680 [C₄₀H₅₇NO₈+H]⁺.

Preparation of 1-(1H-Benzo[d][1,2,3]triazol-1-yl)octadecan-1-one

A solution of stearic acid (2.00 g, 7.03 mmol) in tetrahydrofuran (30mL) was treated with 1H-benzo[d][1,2,3]triazole (921 mg, 7.73 mmol) andN,N′-dicyclohexylcarbodiimide (1.59 g, 7.73 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide1-(1H-benzo[d][1,2,3]triazol-1-yl)octadecan-1-one (3.02 g) as a whitesolid, which was used without purification.

Preparation of (S)-4-(tert-Butoxy)-4-oxo-2-(stearoyloxy)butanoic acid

(S)-4-(tert-Butoxy)-2-hydroxy-4-oxobutanoic acid (247 mg, 1.30 mmol),1-(1H-benzo[d][1,2,3]triazol-1-yl)octadecan-1-one (500 mg, 1.30 mmol),4-(dimethylamino)pyridine (159 mg, 1.30 mmol), and tetrahydrofuran (10mL) were combined and stirred at room temperature under a nitrogenatmosphere for 48 h. After this time, the solvent was removed underreduced pressure, and the residue was partitioned between ethyl acetate(30 mL) and 10% aqueous citric acid. The organic layer was separated andwashed with water (50 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (40 g silica gel column, 0-50% ethylacetate/heptane) to provide of(S)-4-(tert-butoxy)-4-oxo-2-(stearoyloxy)butanoic acid (430 mg, 72%) asa white solid: ¹H NMR (300 MHz, CDCl₃) δ 5.47 (t, J=5.7 Hz, 1H), 2.84(d, J=0.9 Hz, 2H), 2.38 (m, 2H), 1.62 (m, 2H), 1.45 (s, 9H), 1.25 (m,28H), 0.88 (t, J=6.6 Hz, 3H), CO₂H proton not observed.

Preparation of (S)-4-tert-Butyl 1-(2,5-dioxopyrrolidin-1-yl)2-(stearoyloxy)succinate

A solution of (S)-4-(tert-butoxy)-4-oxo-2-(stearoyloxy)butanoic acid(430 mg, 0.942 mmol) in tetrahydrofuran (10 mL) was treated withN-hydroxysuccinimide (119 mg, 1.04 mmol) andN,N′-dicyclohexylcarbodiimide (214 mg, 1.04 mmol) and stirred under anitrogen atmosphere for 4 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-(stearoyloxy)succinate (610 mg) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 5.76 (dd, J=8.1, 1.8 Hz, 1H),2.96 (m, 2H), 2.84 (s, 4H), 2.38 (m, 2H), 1.67 (m, 2H), 1.46 (s, 9H),1.25 (m, 28H), 0.88 (t, J=6.3 Hz, 3H).

Preparation of(S)-1-((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-(2-oxononadecyl)succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (20 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl) 2-(stearoyloxy)succinate(759 mg, 1.37 mmol) in tetrahydrofuran (5 mL). After addition wascomplete, the mixture was warmed to 0° C. After this time, the reactionmixture was treated with saturated aqueous ammonium chloride (20 mL) andextracted with ethyl acetate (2×50 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (40 g silica gelcolumn, 0-20% methanol/methylene chloride) to provide(S)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-(2-oxononadecyl)succinate (782 mg, 74%) as a white solid:ESI MS m/z 840 [C₄₈H₇₃NO₁₁+H]⁺.

Preparation of(S)-3-((((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)carbonyl)-5-oxodocosanoicacid trifluoroacetic acid salt

A solution of(S)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-(2-oxononadecyl)succinate (390 mg, 0.464 mmol) inmethylene chloride (3 mL) was treated with trifluoroacetic acid (3 mL)and stirred under a nitrogen atmosphere at ambient temperature for 1 h.After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (150 g C18 column, 0-100% acetonitrile/water) and freezedried to provide(S)-3-((((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)carbonyl)-5-oxodocosanoicacid trifluoroacetic acid salt (69 mg, 13%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 12.77 (s, 1H), 9.26 (s, 1H), 9.14 (s, 1H), 6.65(q, J=8.1 Hz, 2H), 6.24 (s, 1H), 5.59 (dd, J=6.0, 2.1 Hz, 1H), 5.40 (dd,J=7.8, 4.2 Hz, 1H), 4.92 (s, 1H), 3.04-2.83 (m, 6H), 2.63-2.24 (m, 6H),2.06 (d, J=18.0 Hz, 1H), 1.64-1.52 (m, 3H), 1.25 (m, 31H), 0.85 (t,J=6.9 Hz, 3H); ESI MS m/z 682 [C₄₀H₅₉NO₈+H]⁺.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl 2-acetoxypropanoate

A solution of (S)-2-acetoxypropanoic acid (10.06 g, 76.15 mmol) intetrahydrofuran (300 mL) was treated with N-hydroxysuccinimide (9.71 g,84.4 mmol) and N,N′-dicyclohexylcarbodiimide (17.36 g, 84.14 mmol) andstirred under a nitrogen atmosphere for 4.5 h. After this time, thereaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether, and the combinedfiltrate and washings were concentrated under reduced pressure. Thecrude residue was triturated with 5:1 diethyl ether/methylene chloride(120 mL). The resulting solid was isolated by filtration and washed withdiethyl ether. The combined filtrate and washings were concentratedunder reduced pressure to provide (S)-2,5-dioxopyrrolidin-1-yl2-acetoxypropanoate (18.24 g, quantitative) as an off-white foam: ¹H NMR(300 MHz, CDCl₃) δ 5.41 (t, J=7.2 Hz, 1H), 2.81 (s, 4H), 2.16 (s, 3H),1.67 (d, J=7.2 Hz, 3H).

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-acetoxypropanoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-2,5-dioxopyrrolidin-1-yl 2-acetoxypropanoate (314 mg, 1.37 mmol) intetrahydrofuran (5 mL). After addition was complete, the mixture waswarmed to 0° C. After this time, the reaction mixture was treated withsaturated aqueous ammonium chloride (20 mL) and extracted with ethylacetate (2×25 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-acetoxypropanoate (131 mg, 20%) as a white solid: ESI MS m/z 516[C₂₇H₃₃NO₉+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-acetoxypropanoate trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-acetoxypropanoate (131 mg, 0.254 mmol) in methylene chloride (5.0 mL)was treated with trifluoroacetic acid (3.0 mL) and stirred under anitrogen atmosphere at ambient temperature for 2 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas purified by reversed phase column chromatography (50 g C18 column,0-100% acetonitrile/water) and freeze dried to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-acetoxypropanoate trifluoroacetic acid salt (99 mg, 67%) as a fluffywhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 9.14 (s, 1H),6.65 (q, J=8.1 Hz, 2H), 6.25 (s, 1H), 5.58 (dd, J=6.0, 2.1 Hz, 1H), 5.08(q, J=6.9 Hz, 1H), 4.95 (s, 1H), 3.05 (m, 1H), 2.83 (d, J=4.2 Hz, 3H),2.67-2.24 (m, 6H), 2.11-2.03 (m, 4H), 1.62 (d, J=12.6 Hz, 1H), 1.51 (d,J=7.2 Hz, 3H); ESI MS m/z 416 [C₂₂H₂₅NO₇+H]⁺.

Preparation of (S)-2-(((S)-2-Acetoxypropanoyl)oxy)propanoic acid

(S)-Lactic acid (472 mg, 5.24 mmol), (S)-2,5-dioxopyrrolidin-1-yl2-acetoxypropanoate (1.00 g, 4.36 mmol), 4-(dimethylamino)pyridine (53mg, 0.44 mmol), pyridine (414 mg, 5.24 mmol) and tetrahydrofuran (17 mL)were combined and heated at 80° C. under a nitrogen atmosphere for 24 h.After this time, the solvent was removed under reduced pressure, and theresidue was partitioned between ethyl acetate (20 mL) and 10% aqueouscitric acid. The organic layer was separated and extracted withsaturated aqueous sodium bicarbonate (20 ml). The aqueous phase wascollected and acidified to pH=3 with 6 N hydrochloric acid, and themixture was extracted with ethyl acetate (2×20 mL). The combinedorganics were washed with brine (50 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide(S)-2-(((S)-2-acetoxypropanoyl)oxy)propanoic acid (323 mg, 36%) as acolorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.23-5.08 (m, 2H), 2.14 (s,3H), 1.60-1.48 (m, 6H), CO₂H proton not observed.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-(((S)-2-acetoxypropanoyl)oxy)propanoate

A solution of (S)-2-(((S)-2-acetoxypropanoyl)oxy)propanoic acid (323 mg,1.58 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (200 mg, 1.74 mmol) andN,N′-dicyclohexylcarbodiimide (358 mg, 1.74 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-2,5-dioxopyrrolidin-1-yl2-(((S)-2-acetoxypropanoyl)oxy)propanoate (543 mg) as a colorless oil:¹H NMR (300 MHz, CDCl₃) δ 5.53 (q, J=5.4 Hz, 1H), 5.13 (q, J=5.4 Hz,1H), 2.85 (s, 4H), 2.13 (s, 3H), 1.72 (m, 3H), 1.57 (m, 3H).

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-acetoxypropanoyl)oxy)propanoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (577 mg, 1.44 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.7 mL, 1.7 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-2,5-dioxopyrrolidin-1-yl 2-(((S)-2-acetoxypropanoyl)oxy)propanoate(476 mg, 1.58 mmol) in tetrahydrofuran (5 mL). After addition wascomplete, the mixture was warmed to 0° C. After this time, the reactionmixture was treated with saturated aqueous ammonium chloride (20 mL) andextracted with ethyl acetate (2×50 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (40 g silica gelcolumn, 0-20% methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-acetoxypropanoyl)oxy)propanoate (236 mg, 28%) as a whitesolid: ESI MS m/z 588 [C₃₀H₃₇NO₁₁+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-acetoxypropanoyl)oxy)propanoate trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-acetoxypropanoyl)oxy)propanoate (118 mg, 0.201 mmol) inmethylene chloride (3.0 mL) was treated with trifluoroacetic acid (3.0mL) and stirred under a nitrogen atmosphere at ambient temperature for 2h. After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 0-100% acetonitrile/water) and freezedried to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-acetoxypropanoyl)oxy)propanoate trifluoroacetic acid salt(68.4 mg, 54%) as a fluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.27(s, 1H), 9.14 (s, 1H), 6.65 (q, J=8.1 Hz, 2H), 6.24 (s, 1H), 5.58 (dd,J=5.7, 1.8 Hz, 1H), 5.23 (q, J=6.9 Hz, 1H), 5.07 (q, J=7.2 Hz, 1H), 4.95(s, 1H), 3.05 (m, 1H), 2.82 (s, 3H), 2.63-2.24 (m, 6H), 2.08-2.03 (m,4H), 1.62 (d, J=12.3 Hz, 1H), 1.54 (d, J=7.2 Hz, 3H), 1.47 (d, J=7.2 Hz,3H); ESI MS m/z 488 [C₂₅H₂₉NO₉+H]⁺.

Preparation of (S)-2-(((S)-2-Acetoxypropanoyl)oxy)-2-phenylacetic acid

(S)-Mandelic acid (553 mg, 3.63 mmol), (S)-2,5-dioxopyrrolidin-1-yl2-acetoxypropanoate (1.00 g, 4.36 mmol), 4-(dimethylamino)pyridine (44mg, 0.363 mmol), pyridine (345 mg, 4.36 mmol) and tetrahydrofuran (15mL) were combined and heated at 60° C. under a nitrogen atmosphere for48 h. After this time, the solvent was removed under reduced pressure,and the residue was partitioned between ethyl acetate (20 mL) and 10%aqueous citric acid. The organic layer was separated and extracted withsaturated aqueous sodium bicarbonate (20 ml). The aqueous phase wascollected and acidified to pH=3 with 6 N hydrochloric acid, and themixture was extracted with ethyl acetate (2×20 mL). The combinedorganics were washed with brine (50 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide(S)-2-(((S)-2-acetoxypropanoyl)oxy)-2-phenylacetic acid (1.02 g, 87%) asa colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.46-7.37 (m, 5H), 5.99 (s,1H), 5.19 (q, J=7.2 Hz, 1H), 2.12 (s, 3H), 1.61 (d, J=6.9 Hz, 3H), CO₂Hproton not observed.

Preparation of(S)—(S)-2-((2,5-Dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl2-acetoxypropanoate

A solution of (S)-2-(((S)-2-acetoxypropanoyl)oxy)-2-phenylacetic acid(1.02 g, 3.83 mmol) in tetrahydrofuran (40 mL) was treated withN-hydroxysuccinimide (485 mg, 4.21 mmol) andN,N′-dicyclohexylcarbodiimide (867 mg, 4.21 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide(S)—(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl2-acetoxypropanoate (1.65 g) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ7.56-7.51 (m, 5H), 6.38 (s, 1H), 5.17 (q, J=7.2 Hz, 1H), 2.82 (s, 4H),2.12 (s, 3H), 1.59 (d, J=6.9 Hz, 3H).

Preparation of(S)—(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-acetoxypropanoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)—(S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl2-acetoxypropanoate (498 mg, 1.37 mmol) in tetrahydrofuran (5 mL). Afteraddition was complete, the mixture was warmed to 0° C. After this time,the reaction mixture was treated with saturated aqueous ammoniumchloride (20 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (40 g silica gel column, 0-20% methanol/methylenechloride, then 50 g C18 column, 10-100% acetonitrile/water) to provide(S)—(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-acetoxypropanoate (318 mg, 39%) as a white solid: ESI MS m/z 650[C₃₅H₃₉NO₁₁+H]⁺.

Preparation of(S)—(S)-2-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-acetoxypropanoate trifluoroacetic acid salt

A solution of(S)—(S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-acetoxypropanoate (159 mg, 0.245 mmol) in methylene chloride (5.0 mL)was treated with trifluoroacetic acid (3.0 mL) and stirred under anitrogen atmosphere at ambient temperature for 1 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas purified by reversed phase column chromatography (50 g C18 column,0-100% acetonitrile/water) and freeze dried to provide(S)—(S)-2-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl2-acetoxypropanoate trifluoroacetic acid salt (90 mg, 52%) as a fluffywhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 9.12 (s, 1H),7.60-7.55 (m, 2H), 7.52-7.46 (m, 3H), 6.65 (q, J=8.1 Hz, 2H), 6.24 (s,1H), 6.21 (s, 1H), 5.58 (dd, J=6.0, 2.1 Hz, 1H), 5.15 (q, J=6.9 Hz, 1H),4.86 (s, 1H), 3.03 (m, 1H), 2.82 (s, 3H), 2.63-2.22 (m, 6H), 2.08-2.02(m, 4H), 1.62 (d, J=13.5 Hz, 1H), 1.54 (d, J=7.2 Hz, 3H); ESI MS m/z 550[C₃₀H₃₁NO₉+H]⁺.

Preparation of(S)-2-(((S)-2-Acetoxypropanoyl)oxy)-4-(tert-butoxy)-4-oxobutanoic acid

(S)-4-(tert-Butoxy)-2-hydroxy-4-oxobutanoic acid (692 mg, 3.64 mmol),(S)-2,5-dioxopyrrolidin-1-yl 2-acetoxypropanoate (1.00 g, 4.36 mmol),4-(dimethylamino)pyridine (44 mg, 0.36 mmol), pyridine (345 mg, 4.36mmol), and tetrahydrofuran (17 mL) were combined and heated at 80° C.under a nitrogen atmosphere for 24 h. After this time, the solvent wasremoved under reduced pressure, and the residue was partitioned betweenethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer wasseparated and extracted with saturated aqueous sodium bicarbonate (20ml). The aqueous phase was collected and acidified to pH=3 with 6 Nhydrochloric acid, and the mixture was extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(S)-2-(((S)-2-acetoxypropanoyl)oxy)-4-(tert-butoxy)-4-oxobutanoic acid(1.05 g, 79%) as a brown oil: ¹H NMR (300 MHz, CDCl₃) δ 5.52 (t, J=5.7Hz, 1H), 5.12 (q, J=7.2 Hz, 1H), 2.90-2.76 (m, 2H), 2.13 (s, 3H), 1.55(d, J=7.2 Hz, 3H), 1.46 (s, 9H), CO₂H proton not observed.

Preparation of (S)-4-tert-Butyl 1-(2,5-dioxopyrrolidin-1-yl)2-(((S)-2-acetoxypropanoyl)oxy)succinate

A solution of(S)-2-(((S)-2-acetoxypropanoyl)oxy)-4-(tert-butoxy)-4-oxobutanoic acid(1.05 g, 3.45 mmol) in tetrahydrofuran (40 mL) was treated withN-hydroxysuccinimide (436 mg, 3.80 mmol) andN,N′-dicyclohexylcarbodiimide (783 mg, 3.80 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-(((S)-2-acetoxypropanoyl)oxy)succinate(1.80 g) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 5.84 (dd, J=7.2,5.1 Hz, 1H), 5.12 (q, J=7.2 Hz, 1H), 3.02-2.92 (m, 2H), 2.84 (s, 4H),2.13 (s, 3H), 1.54 (d, J=7.2 Hz, 3H), 1.45 (s, 9H).

Preparation of(S)-1-((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-((S)-3-acetoxy-2-oxobutyl)succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)2-(((S)-2-acetoxypropanoyl)oxy)succinate (550 mg, 1.37 mmol) intetrahydrofuran (5 mL). After addition was complete, the mixture waswarmed to 0° C. After this time, the reaction mixture was treated withsaturated aqueous ammonium chloride (20 mL) and extracted with ethylacetate (2×50 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-((S)-3-acetoxy-2-oxobutyl)succinate (318 mg, 39%) as awhite solid: ESI MS m/z 688 [C₃₅H₄₅NO₁₃+H]r.

Preparation of(3S,6S)-6-Acetoxy-3-((((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)carbonyl)-5-oxoheptanoicacid trifluoroacetic acid salt

A solution of(S)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-((S)-3-acetoxy-2-oxobutyl)succinate (126 mg, 0.183 mmol)in methylene chloride (3 mL) was treated with trifluoroacetic acid (3mL) and stirred under a nitrogen atmosphere at ambient temperature for 3h. After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 0-100% acetonitrile/water with 0.1%trifluoroacetic acid) and freeze dried to provide(3S,6S)-6-acetoxy-3-((((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)carbonyl)-5-oxoheptanoicacid trifluoroacetic acid salt (73 mg, 56%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 12.82 (s, 1H), 9.27 (s, 1H), 9.15 (s, 1H), 6.65(apparent q, J=8.1 Hz, 2H), 6.25 (s, 1H), 5.59 (dd, J=6.0, 2.1 Hz, 1H),5.50 (t, J=5.4 Hz, 1H), 5.08 (q, J=7.2 Hz, 1H), 4.91 (s, 1H), 3.04 (m,1H), 2.95 (d, J=6.0 Hz, 2H), 2.84 (d, J=4.5 Hz, 3H), 2.67-2.25 (m, 8H),2.08-2.03 (m, 4H), 1.62 (d, J=11.7 Hz, 1H), 1.46 (d, J=6.9 Hz, 3H); ESIMS m/z 530 [C₂₇H₃₁NO₁₀+H]⁺.

Preparation of (S)-2-(((S)-2-(Oleoyloxy)propanoyl)oxy)propanoic acid

A solution of (S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yloleate (3.49 g, 7.73 mmol), (S)-lactic acid (764 mg, 8.48 mmol), and4-dimethylaminopyridine (100 mg, 0.819 mmol) in tetrahydrofuran (35 mL)was treated with pyridine (0.69 g, 8.6 mmol) and heated at 50° C. undera nitrogen atmosphere for 64 h. After this time, the reaction mixturewas cooled to room temperature and concentrated under reduced pressure.The residue was dissolved in methylene chloride (100 mL) and washed withaqueous 10% citric acid (2×50 mL). The organic layer was dried oversodium sulfate, filtered, and concentrated. The crude residue waspurified by column chromatography (silica gel, 0-10% methanol/methylenechloride) to provide (S)-2-(((S)-2-(oleoyloxy)propanoyl)oxy)propanoicacid (835 mg, 25%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ5.36-5.29 (m, 2H), 5.24-5.08 (m, 2H), 2.41-2.35 (m, 2H), 2.02-1.98 (m,4H), 1.67-1.60 (m, 2H), 1.58-1.52 (m, 6H), 1.30-1.27 (m, 20H), 0.88 (t,J=6.6 Hz, 3H), CO₂H proton not observed.

Preparation of(S)-1-(((S)-1-((2,5-Dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yloleate

A solution of (S)-2-(((S)-2-(oleoyloxy)propanoyl)oxy)propanoic acid(0.83 g, 2.0 mmol) in tetrahydrofuran (10 mL) was treated withN-hydroxysuccinimide (262 mg, 2.28 mmol) andN,N′-dicyclohexylcarbodiimide (446 mg, 2.16 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide(S)-1-(((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yloleate (1.07 g, quantitative) as a white semi-solid: ¹H NMR (300 MHz,CDCl₃) δ 5.52 (q, J=7.2 Hz, 1H), 5.38-5.33 (m, 2H), 5.11 (q, J=7.2 Hz,1H), 2.84 (br s, 4H), 2.42-2.35 (m, 2H), 2.02-1.98 (m, 4H), 1.72-1.53(m, 8H), 1.30-1.27 (m, 20H), 0.88 (t, J=6.6 Hz, 3H).

Preparation of(S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yloleate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (350 mg, 0.872 mmol) in tetrahydrofuran (10 mL) was cooled to0° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (0.95 mL, 0.95 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 25 min andthen at ambient temperature for 25 min. The mixture was re-cooled to−78° C., and a solution of(S)-1-(((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yloleate (500 mg, 0.956 mmol) in tetrahydrofuran (5 mL) was added. Themixture was allowed to warm to 0° C. over 2 h. After this time, themixture was treated with saturated aqueous ammonium chloride (10 mL) andextracted with ethyl acetate (2×25 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (40 g silica gelcolumn, 0-20% methanol/methylene chloride) to provide(S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yloleate (628 mg, 88%) as a white solid: ESI MS m/z 810 [C₄₆H₆₇NO₁₁+H]⁺.

Preparation of(S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yloleate trifluoroacetic acid salt

A solution of(S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yloleate (314 mg, 0.388 mmol) in methylene chloride (5.0 mL) was treatedwith trifluoroacetic acid (5.0 mL) and stirred under a nitrogenatmosphere at ambient temperature for 3 h. After this time, the reactionmixture was concentrated under reduced pressure. The residue waspurified by reversed phase column chromatography (150 g C18 column,0-100% acetonitrile/water with 0.1% trifluoroacetic acid) and freezedried to provide(S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yloleate trifluoroacetic acid salt (63 mg, 18%) as a fluffy white solid:¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 9.14 (s, 1H), 6.65 (apparentq, J=8.1 Hz, 2H), 6.23 (s, 1H), 5.57 (dd, J=6.3, 2.1 Hz, 1H), 5.32 (t,J=4.5 Hz, 1H), 5.22 (q, J=6.9 Hz, 1H), 5.08 (q, J=7.2 Hz, 1H), 4.95 (s,1H), 3.06 (m, 1H), 2.84 (d, J=4.5 Hz, 3H), 2.63-2.25 (m, 8H), 2.09-1.95(m, 4H), 1.64-1.46 (m, 10H), 1.23 (m, 21H), 0.85 (t, J=6.6 Hz, 3H); ESIMS m/z 710 [C₄₁H₅₉NO₉+H]⁺.

Preparation of (S)-tert-Butyl 2-acetoxy-2-phenylacetate

A mixture of (S)-2-acetoxy-2-phenylacetic acid (22.0 g, 104 mmol) andtert-butanol (19.0 g, 257 mmol) in methylene chloride (150 mL) at 0° C.was treated with N,N′-dicyclohexylcarbodiimide (28.0 g, 136 mmol). Afterstirring for 1 h, the ice bath was removed and the reaction mixture wasstirred at ambient temperature for 18 h. After this time, the mixturewas filtered and the filtrate was concentrated under reduced pressure.The residue was purified by column chromatography (330 g silica gelcolumn, 5-20% ethyl acetate/heptane) to provide (S)-tert-butyl2-acetoxy-2-phenylacetate (14.4 g, 52%): ¹H NMR (300 MHz, CDCl₃) δ7.48-7.43 (m, 2H), 7.40-7.35 (m, 3H), 5.80 (s, 1H), 2.18 (s, 3H), 1.40(s, 9H).

Preparation of (S)-tert-Butyl 2-hydroxy-2-phenylacetate

A solution of (S)-tert-butyl 2-acetoxy-2-phenylacetate (14.4 g, 54.1mmol) in methanol (15 mL) was cooled to 0° C. and treated with asolution of sodium bicarbonate (22.5 g, 163 mmol) in water/methanol(3:2, 145 mL). The reaction mixture was stirred at 0° C. for 2 h, andthen neutralized by addition of citric acid (10 g, 52 mmol). The mixturewas partially concentrated under reduced pressure and then extractedwith methylene chloride. The organic layer was washed with water andbrine, dried over sodum sulfate, filtered, and concentrated underreduced pressure to provide (S)-tert-butyl 2-hydroxy-2-phenylacetate(11.2 g), which was used without purification: ¹H NMR (300 MHz, CDCl₃) δ7.43-7.29 (m, 5H), 5.03 (d, J=6.0 Hz, 1H), 3.50 (d, J=6.0 Hz, 1H), 1.41(s, 9H).

Preparation of(S)-4-(2-(tert-Butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoic acid

A solution of (S)-tert-butyl 2-hydroxy-2-phenylacetate (3.15 g, 15.1mmol) in tetrahydrofuran (35 mL) at 0° C. was treated with a 1.0 Msolution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (16 mL,16 mmol), and the mixture was stirred for 10 min. After this time, asolution of succinic anhydride (1.33 g, 16.6 mmol) in tetrahydrofuran(25 mL) was added, and the mixture was stirred at 0° C. for 1.5 h. Afterthis time, the mixture was poured into a saturated solution of ammoniumchloride and extracted with ethyl acetate. The organic extract was driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide (S)-4-(2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (4.60 g): ESI MS m/z 634 [C₁₆H₂₀O₆+NH₄].

Preparation of (S)-2-(tert-Butoxy)-2-oxo-1-phenylethyl(2,5-dioxopyrrolidin-1-yl) succinate

A mixture of (S)-4-(2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (4.60 g, 15.0 mmol) and N-hydroxysuccinimide (1.90 g, 16.5 mmol) intetrahydrofuran (75 mL) at 0° C. was treated withN,N′-dicyclohexylcarbodiimide (3.40 g, 16.5 mmol). The ice bath wasremoved, and the reaction mixture was stirred at ambient temperature for4 h. After this time, diethyl ether (75 mL) was added, and the mixturewas filtered. The filtrate was concentrated under reduced pressure toprovide (S)-2-(tert-butoxy)-2-oxo-1-phenylethyl(2,5-dioxopyrrolidin-1-yl) succinate (10.0 g) that was used withoutpurification: ¹H NMR (300 MHz, CDCl₃) δ 7.47-7.42 (m, 2H), 7.42-7.35 (m,3H), 5.84 (s, 1H), 3.06-2.98 (m, 2H), 2.93-2.88 (m, 2H), 2.83 (s, 4H),1.39 (s, 9H).

Preparation of (S)-2-(tert-Butoxy)-2-oxo-1-phenylethyl((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (490 mg, 1.22 mmol) in tetrahydrofuran (10 mL) was cooled to−10° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.4 mL, 1.4 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to −10° C. and(S)-2-(tert-butoxy)-2-oxo-1-phenylethyl (2,5-dioxopyrrolidin-1-yl)succinate (650 mg, 1.6 mmol) was added in one portion. The mixture wasstirred at −10° C. to ambient temperature over 1.5 h. After this time,the reaction mixture was cooled in an ice bath, treated with saturatedaqueous ammonium chloride, and extracted with ethyl acetate. Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 5-100%acetonitrile/water) to provide (S)-2-(tert-butoxy)-2-oxo-1-phenylethyl((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)succinate (530 mg, 62%): ESI MS m/z 692 [C₃₈H₄₅NO₁₁+H]⁺.

Preparation of(S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt

A solution of (S)-2-(tert-butoxy)-2-oxo-1-phenylethyl((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)succinate (530 mg, 0.77 mmol) in methylene chloride (10 mL) was treatedwith trifluoroacetic acid (4 mL) and stirred at ambient temperature for2.5 h. After this time, the reaction mixture was concentrated underreduced pressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 3-20% acetonitrile/water, with 0.1%trifluoracetic acid) and freeze dried to provide(S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt (121 mg, 23%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.15 (br s, 1H), 7.50-7.44 (m,2H), 7.44-7.40 (m, 3H), 6.68 (d, J=8.2 Hz, 1H), 6.62 (d, J=8.2 Hz, 1H),6.22 (s, 1H), 5.85 (s, 1H), 5.49 (dd, J=6.0, 1.9 Hz, 1H), 4.93 (s, 1H),3.61 (d, J=6.3 Hz, 1H), 3.12-3.01 (m, 2H), 2.84 (s, 3H), 2.79-2.70 (m,4H), 2.70-2.58 (m, 1H), 2.42 (dd, J=13.3, 4.7 Hz, 1H), 2.25 (dd, J=17.1,7.1 Hz, 1H), 2.04 (d, J=17.1 Hz, 1H), 1.61 (d, J=11.2 Hz, 1H), CO₂Hproton not observed, one proton obscured by solvent peaks; ESI MS m/z536 [C₂₉H₂₉NO₉+H]⁺; HPLC (Method A) 98.9% (AUC), t_(R)=8.55 min.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-acetoxy-2-phenylacetate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (360 mg, 0.90 mmol) in tetrahydrofuran (8 mL) was cooled to 0°C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.0 mL, 1.0 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to 0° C.,and(S)-2,5-dioxopyrrolidin-1-yl 2-acetoxy-2-phenylacetate (340 mg, 1.1mmol) was added in one portion. The mixture was stirred at 0° C. toambient temperature over 1 h. After this time, the reaction mixture wascooled in an ice bath, treated with saturated aqueous ammonium chloride,and extracted with ethyl acetate. The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 5-100% acetonitrile/water) to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-acetoxy-2-phenylacetate (235 mg, 45%): ESI MS m/z 578 [C₃₂H₃₅NO₉+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-acetoxy-2-phenylacetate trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-acetoxy-2-phenylacetate (230 mg, 0.40 mmol) in methylene chloride (6mL) was treated with trifluoroacetic acid (2.5 mL) and stirred atambient temperature for 2 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 5-20%acetonitrile/water, with 0.1% trifluoracetic acid) and freeze dried toprovide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-acetoxy-2-phenylacetate trifluoroacetic acid salt (121 mg, 23%) as afluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s, 1H), 9.15 (brs, 1H), 7.60-7.51 (m, 2H), 7.51-7.43 (m, 3H), 6.68 (d, J=8.1 Hz, 1H),6.61 (d, J=8.1 Hz, 1H), 6.27 (s, 1H), 6.08 (s, 1H), 5.58 (dd, J=6.0, 1.9Hz, 1H), 4.87 (s, 1H), 3.61 (d, J=6.1 Hz, 1H), 3.11-3.00 (m, 2H), 2.83(d, J=4.6 Hz, 3H), 2.70-2.55 (m, 1H), 2.42 (dd, J=12.8, 4.2 Hz, 1H),2.26 (dd, J=18.0, 6.1 Hz, 1H), 2.17 (s, 3H), 2.05 (d, J=18.0 Hz, 1H),1.60 (d, J=11.1 Hz, 1H), one proton obscured by solvent peaks; ESI MSm/z 478 [C₂₇H₂₇NO₇+H]⁺; HPLC (Method A) 98.7% (AUC), t_(R)=9.03 min.

Preparation of (3S,3′S)-Di-tert-butyl4,4′-(((((4R,4aS,7aR,12b)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(3-oxopropane-3,1-diyl))bis(azanediyl))bis(3-((tert-butoxycarbonyl)oxy)-4-oxobutanoate)

A solution of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((tert-butoxycarbonyl)amino)propanoate) (800 mg, 1.06 mmol) inmethylene chloride (12 mL) was treated with trifluoroacetic acid (1.2mL), and the mixture was stirred at room temperature for 2 h. After thistime, LC-MS analysis of the reaction mixture showed cleavage of the Bocprotecting groups. N,N-Diisopropylethylamine was added slowly until thereaction mixture tested basic by pH paper analysis (3 mL of base added).The mixture was treated with (S)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate (900mg, 2.32 mmol) in one portion and stirred at room temperature for 2 h.After this time, the mixture was diluted with ethyl acetate and washedwater and brine. The organic extracts were dried over sodium sulfate,filtered, and concentrated. The residue was purified by reversed phasecolumn chromatography (50 g C18 column, 5-100% acetonitrile/water) toprovide (3S,3′S)-di-tert-butyl4,4′-(((((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(3-oxopropane-3,1-diyl))bis(azanediyl))bis(3-((tert-butoxycarbonyl)oxy)-4-oxobutanoate)

mg, 40%): ESI MS m/z 1102 [C₅₅H₈₃N₃O₁₈Si+H]⁺.

Preparation of (3S,3′S)-Di-tert-butyl4,4′-(((((4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(3-oxopropane-3,1-diyl))bis(azanediyl))bis(3-((tert-butoxycarbonyl)oxy)-4-oxobutanoate)trifluoroacetic acid salt

A solution of (3S,3′S)-di-tert-butyl4,4′-(((((4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(3-oxopropane-3,1-diyl))bis(azanediyl))bis(3-((tert-butoxycarbonyl)oxy)-4-oxobutanoate)(470 mg, 0.43 mmol) in tetrahydrofuran (8 mL) was treated with water (5mL) followed by trifluoroacetic acid (3 mL), and the mixture was stirredat room temperature for 3 h. After this time, the mixture wasconcentrated, and the residue was azeotroped with toluene to provide(3S,3′S)-di-tert-butyl4,4′-(((((4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(3-oxopropane-3,1-diyl))bis(azanediyl))bis(3-((tert-butoxycarbonyl)oxy)-4-oxobutanoate)trifluoroacetic acid salt (440 mg, crude) that was used withoutpurification: ESI MS m/z 988 [C₄₉H₆₉N₃O₁₈+H]⁺.

Preparation of(3S,3′S)-4,4′-(((((4R,4aS,7aR,12bS)-9-Hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(3-oxopropane-3,1-diyl))bis(azanediyl))bis(3-hydroxy-4-oxobutanoicacid) trifluoroacetic acid salt

A solution of (3S,3′S)-di-tert-butyl4,4′-(((((4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(3-oxopropane-3,1-diyl))bis(azanediyl))bis(3-((tert-butoxycarbonyl)oxy)-4-oxobutanoate)(440 mg) in methylene chloride (6 mL) was treated with trifluoroaceticacid (2.5 mL) and stirred at ambient temperature for 2 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 5-20% acetonitrile/water, with 0.1% trifluoracetic acid) andfreeze dried to provide(3S,3′S)-4,4′-(((((4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(3-oxopropane-3,1-diyl))bis(azanediyl))bis(3-hydroxy-4-oxobutanoicacid) trifluoroacetic acid salt (167 mg, 53% over two steps) as a fluffywhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.55 (br s, 2H), 8.03-7.97 (m,2H), 6.73 (d, J=8.2 Hz, 1H), 6.66 (d, J=8.2 Hz, 1H), 5.50 (dd, J=6.7,1.8 Hz, 1H), 5.06 (s, 1H), 4.73 (d, J=6.0 Hz, 1H), 4.26-4.21 (m, 2H),3.45-3.13 (m, 10 OH), 3.08-2.90 (m, 4H), 2.86-2.70 (m, 1H), 2.70-2.53(m, 5H), 2.45-2.25 (m, 3H), 2.09 (d, J=18.6 Hz, 1H), 1.78 (d, J=13.5 Hz,1H), CO₂H protons not observed; ESI MS m/z 676 [C₃₁H₃₇N₃O₁₄+H]⁺; HPLC(Method A) 98.6% (AUC), t_(R)=6.42 min.

Preparation of (S)-2-Acetoxy-4-(tert-butoxy)-4-oxobutanoic acid

(S)-4-(tert-Butoxy)-2-hydroxy-4-oxobutanoic acid (4.88 g, 25.7 mmol),acetyl chloride (2.22 g, 28.2 mmol), N,N-diisopropylethylamine (3.99 g,30.8 mmol), and methylene chloride (200 mL) were combined at 0° C. andstirred at room temperature under a nitrogen atmosphere for 16 h. Afterthis time, 10% aqueous citric acid (100 mL) was added. The organic layerwas separated and extracted with methylene chloride (2×100 mL). Thecombined organics were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoic acid (4.59 g, 76%) as alight yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.46 (m, 1H), 2.83 (m, 2H),2.14 (s, 3H), 1.46 (s, 9H), CO₂H proton not observed.

Preparation of (S)-Di-tert-butyl 2-acetoxysuccinate

A solution of (S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoic acid (4.59 g,19.8 mmol) and tert-butanol (3.22 g, 43.5 mmol) in methylene chloride(70 mL) was treated with N,N′-dicyclohexylcarbodiimide (5.31 g, 25.7mmol) and 4-(dimethylamino)pyridine (798 mg, 6.53 mmol) at 0° C. andstirred at room temperature under a nitrogen atmosphere for 16 h. Afterthis time, the reaction mixture was filtered to remove the soliddicyclohexylurea byproduct. The solid was washed with diethyl ether (100mL), and the combined filtrate and washings were concentrated underreduced pressure. The crude residue was purified by columnchromatography (80 g silica gel column, 0-30% ethyl acetate/heptane) toprovide (S)-di-tert-butyl 2-acetoxysuccinate (3.44 g, 60%) as acolorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.30 (dd, J=7.5, 5.4 Hz, 1H),2.75 (m, 2H), 2.13 (s, 3H), 1.46 (s, 18H).

Preparation of (S)-Di-tert-butyl 2-hydroxysuccinate

(S)-Di-tert-butyl 2-acetoxysuccinate (3.44 g, 11.9 mmol), potassiumcarbonate (4.94 g, 35.8 mmol), methanol (240 mL) and water (40 mL) werecombined and stirred at 0° C. for 4 h. After this time, water (200 mL)was added, and the aqueous solution was extracted with methylenechloride (2×200 mL). The combined organics were washed with brine (50mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide (S)-di-tert-butyl 2-hydroxysuccinate (2.71 g, 92%)as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 4.30 (dd, J=10.2, 5.7 Hz,1H), 3.21 (d, J=5.4 Hz, 1H), 2.77-2.60 (m, 2H), 1.45 (s, 9H), 1.42 (s,9H).

Preparation of(S)-4-((1,4-Di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoic acid

(S)-Di-tert-butyl 2-hydroxysuccinate (428 mg, 1.74 mmol),dihydrofuran-2,5-dione (414 mg, 4.14 mmol), N,N-diisopropylethylamine(535 mg, 4.14 mmol), and methylene chloride (10 mL) were combined andstirred at room temperature under a nitrogen atmosphere for 16 h. Afterthis time, 10% aqueous citric acid (100 mL) was added. The organic layerwas separated and extracted with methylene chloride (2×50 mL). Thecombined organics were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(S)-4-((1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoic acid(534 mg, 95%) as a brown oil: ¹H NMR (300 MHz, CDCl₃) δ 5.32 (dd, J=7.5,5.1 Hz, 1H), 2.77-2.66 (m, 6H), 1.46 (s, 18H), CO₂H proton not observed.

Preparation of (S)-Di-tert-butyl2-((4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanoyl)oxy)succinate

A solution of(S)-4-((1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoic acid(534 mg, 1.38 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (159 mg, 1.38 mmol) andN,N′-dicyclohexylcarbodiimide (284 mg, 1.38 mmol) and stirred under anitrogen atmosphere for 3 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-di-tert-butyl2-((4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanoyl)oxy)succinate (684mg) as a brown oil: ¹H NMR (300 MHz, CDCl₃) δ 5.34 (dd, J=6.9, 5.7 Hz,1H), 3.01-2.96 (m, 2H), 2.87-2.70 (m, 8H), 1.44 (s, 18H).

Preparation (S)-Di-tert-butyl2-((4-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (280 mg, 0.698 mmol) in tetrahydrofuran (5 mL) was cooled to0° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (0.78 mL, 0.78 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 25 min andthen at ambient temperature for 25 min. The mixture was re-cooled to−78° C. and a solution of (S)-di-tert-butyl2-((4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanoyl)oxy)succinate (340mg, 0.767 mmol) in tetrahydrofuran (3 mL) was added. The mixture wasallowed to warm to 0° C. over 2 h and then treated with saturatedaqueous ammonium chloride (10 mL) and extracted with ethyl acetate (2×25mL). The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (40 g, silica gel, 0-20% methanol/methylenechloride, then 50 g, C18, 10-100% acetonitrile/water) to provide(S)-di-tert-butyl2-((4-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinate(137 mg, 26%) as a colorless oil: ESI MS m/z 730 [C₃₈H₅₁NO₁₃+H]⁺.

Preparation of(S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid trifluoroacetic acid salt

A solution of (S)-di-tert-butyl2-((4-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinate(137 mg, 0.188 mmol) in methylene chloride (3 mL) was treated withtrifluoroacetic acid (3 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid trifluoroacetic acid salt (85 mg, 76%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 12.3 (s, 1H), 12.6 (s, 1H), 9.30 (s, 1H), 9.14(s, 1H), 6.65 (apparent q, J=8.1 Hz, 2H), 6.22 (s, 1H), 5.53 (dd, J=6.3,2.1 Hz, 1H), 5.23 (dd, J=7.8, 4.5 Hz, 1H), 4.95 (s, 1H), 3.06 (m, 1H),2.91-2.66 (m, 11H), 2.47 (m, 3H), 2.27 (m, 1H), 2.06 (d, J=18.0 Hz, 1H),1.63 (d, J=11.7 Hz, 1H); ESI MS m/z 518 [C₂₅H₂₇NO₁₁+H]⁺; HPLC (MethodA) >99% (AUC), t_(R)=6.80 min.

Preparation of (S)-2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid

A solution of (S)-malic acid (30.28 g, 225.8 mmol) and pyridiniump-toluenesulfonate (5.16 g, 20.5 mmol) in acetone (17 mL) was cooled inan ice bath and treated with 2-methoxyprop-1-ene (85.0 mL, 888 mmol)under a nitrogen atmosphere. After 30 min, the ice bath was removed, andthe mixture was heated at 35° C. for 16 h. After this time, the reactionmixture was cooled to room temperature and concentrated under reducedpressure. The residue was dissolved in ethyl acetate (500 mL), washedwith 1:1 brine/water (4×200 mL), dried over sodium sulfate, filtered,and partially concentrated under reduced pressure to a volume ofapproximately 200 mL. The solution was treated with heptanes (200 mL)and cooled in an ice bath for 1 h. The resulting solids were isolated byfiltration and washed with heptanes to provide(S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (23.14 g, 59%)as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.61 (s, 1H), 4.79 (dd,J=5.1, 4.8 Hz, 1H), 2.83-2.68 (m, 2H), 1.53 (s, 3H), 1.52 (s, 3H).

Preparation of (S)-Benzyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate

A solution of (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid(10.08 g, 57.88 mmol) in methylene chloride (290 mL) was treated withbenzyl alcohol (9.0 mL, 87 mmol), N,N′-dicyclohexylcarbodiimide (14.3 g,69.2 mmol), and 4-dimethylaminopyridine (2.12 g, 17.4 mmol) and stirredunder a nitrogen atmosphere for 1.5 h. After this time, the reactionmixture was filtered to remove the solid dicyclohexylurea byproduct. Thesolid was washed with methylene chloride, and the combined filtrate andwashings were concentrated under reduced pressure. The crude residue waspurified by column chromatography (silica gel, 0-20% ethylacetate/heptanes) to provide (S)-benzyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (8.63 g, 56%) as a whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.41-7.30 (m, 5H), 5.13 (dd, J=14.4,12.3 Hz, 2H), 4.87 (t, J=4.8 Hz, 1H), 3.02-2.89 (m, 2H), 1.52 (s, 3H),1.49 (s, 3H).

Preparation of (S)-4-(Benzyloxy)-2-hydroxy-4-oxobutanoic acid

A solution of (S)-benzyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate(8.63 g, 32.7 mmol) in acetic acid (50 mL) and water (25 mL) was heatedat 60° C. for 1.5 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in waterand freeze dried to provide (S)-4-(benzyloxy)-2-hydroxy-4-oxobutanoicacid (7.32 g, quantitative) as a white solid: ¹H NMR (300 MHz, DMSO-d₆)δ 12.57 (br s, 1H), 7.40-7.29 (m, 5H), 5.57 (br s, 1H), 5.11 (s, 2H),4.33 (dd, J=7.8, 4.8 Hz, 1H), 2.77 (dd, J=15.6, 4.8 Hz, 1H), 2.61 (dd,J=15.6, 7.8 Hz, 1H); ESI MS m/z 223 [C₁₁H₁₂O₅−H]⁻.

Preparation of (S)-2-Acetoxy-4-(benzyloxy)-4-oxobutanoic acid

A solution of (S)-4-(benzyloxy)-2-hydroxy-4-oxobutanoic acid (3.00 g,13.4 mmol) in methylene chloride (15 mL) was treated with acetic acid (3mL) and cooled in an ice bath under a nitrogen atmosphere. The solutionwas treated dropwise with acetyl chloride (1.05 mL, 14.8 mmol). After 15min, the ice bath was removed, and the mixture was stirred at ambienttemperature for 16 h. After this time, the reaction mixture wasconcentrated under reduced pressure and dried under vacuum to provide(S)-2-acetoxy-4-(benzyloxy)-4-oxobutanoic acid (4.12 g, quantitative) asa colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 7.39-7.33 (m, 5H), 5.25(dd, J=8.1, 4.5 Hz, 1H), 5.14 (dd, J=14.4, 12.6 Hz, 2H), 3.00 (dd,J=16.5, 4.5 Hz, 1H), 2.89 (dd, J=16.5, 8.1 Hz, 1H), 2.02 (s, 3H), CO₂Hproton not observed.

Preparation of (S)-4-Benzyl 1-tert-butyl 2-acetoxysuccinate

A solution of (S)-2-acetoxy-4-(benzyloxy)-4-oxobutanoic acid (3.57 g,13.4 mmol) in methylene chloride (60 mL) was treated with tert-butanol(4.5 mL, 47 mmol), N,N′-dicyclohexylcarbodiimide (4.30 g, 20.8 mmol),and 4-dimethylaminopyridine (462 mg, 3.78 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (silica gel, 0-20% ethyl acetate/heptanes) toprovide (S)-4-benzyl 1-tert-butyl 2-acetoxysuccinate (2.78 g, 64%) as acolorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 7.42-7.30 (m, 5H), 5.19-5.14(m, 3H), 3.00-2.85 (m, 2H), 2.03 (s, 3H), 1.37 (s, 9H).

Preparation of (S)-3-Acetoxy-4-(tert-butoxy)-4-oxobutanoic acid

A solution of (S)-4-benzyl 1-tert-butyl 2-acetoxysuccinate (1.02 g, 3.16mmol) in ethanol (30 mL) was sparged with nitrogen gas for 30 min. Thesolution was treated with 5% palladium on carbon (214 mg) and spargedwith hydrogen gas for 5 min. The mixture was stirred under a hydrogenatmosphere for 2 h. After this time, the reaction mixture was spargedwith nitrogen gas for 5 min and filtered through diatomaceous earth. Thefiltrate was concentrated under reduced pressure to provide(S)-3-acetoxy-4-(tert-butoxy)-4-oxobutanoic acid (731 mg, 99%) as acolorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 12.74 (br s, 1H), 5.10 (dd,J=8.1, 4.8 Hz, 1H), 2.81-2.64 (m, 2H), 2.06 (s, 3H), 1.40 (s, 9H).

Preparation of (S)-1-tert-Butyl 4-(2,5-dioxopyrrolidin-1-yl)2-acetoxysuccinate

A solution of (S)-3-acetoxy-4-(tert-butoxy)-4-oxobutanoic acid (725 mg,3.12 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (396 mg, 3.44 mmol) andN,N′-dicyclohexylcarbodiimide (709 mg, 3.44 mmol) and stirred under anitrogen atmosphere for 6 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide (S)-1-tert-butyl4-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (1.25 g, quantitative)as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 5.28 (dd, J=7.5, 4.8Hz, 1H), 3.39-3.22 (m, 2H), 2.82 (s, 4H), 2.08 (s, 3H), 1.41 (s, 9H).

Preparation of(S)-4-((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)1-tert-butyl 2-acetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (660 mg, 1.64 mmol) in tetrahydrofuran (10 mL) was cooled to0° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.8 mL, 1.8 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 25 min andthen at ambient temperature for 25 min. The mixture was re-cooled to−78° C., and a solution of (S)-1-tert-butyl 4-(2,5-dioxopyrrolidin-1-yl)2-acetoxysuccinate (600 mg, 1.82 mmol) in tetrahydrofuran (5 mL) wasadded. The mixture was allowed to warm to 0° C. over 2 h. After thistime, the mixture was treated with saturated aqueous ammonium chloride(10 mL) and extracted with ethyl acetate (2×25 mL). The combinedorganics were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude residue was purified by columnchromatography (40 g silica gel column, 0-20% methanol/methylenechloride, then 50 g C18 column, 10-100% acetonitrile/water) to provide(S)-4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)1-tert-butyl 2-acetoxysuccinate (332 mg, 32%) as a white solid: ESI MSm/z 616 [C₃₂H₄₁NO₁₁+H]⁺.

Preparation of(S)-2-Acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(S)-4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)1-tert-butyl 2-acetoxysuccinate (166 mg, 0.270 mmol) in methylenechloride (3 mL) was treated with trifluoroacetic acid (3 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 1 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 0-100% acetonitrile/water with 0.1% trifluoroacetic acid) andfreeze dried to provide(S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (100 mg, 60%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 13.4 (br s, 1H), 9.29 (s, 1H), 9.14 (br s, 1H),6.65 (apparent q, J=8.1 Hz, 2H), 6.24 (s, 1H), 5.55 (dd, J=5.7, 2.1 Hz,1H), 5.28 (dd, J=8.4, 4.5 Hz, 1H), 4.96 (s, 1H), 3.12-2.94 (m, 4H), 2.84(d, J=3.6 Hz, 3H), 2.67-2.42 (m, 4H), 2.27 (dd, J=17.7, 6.0 Hz, 1H),2.09-2.03 (m, 4H), 1.63 (d, J=11.7 Hz, 1H); ESI MS m/z 460[C₂₃H₂₅NO₉+H]⁺; HPLC (Method A) 96.8% (AUC), t_(R)=6.88 min.

Preparation of (S)-2-Acetoxy-2-phenylacetic acid

A solution of (S)-2-hydroxy-2-phenylacetic acid (16.4 g, 108 mmol) inacetic acid (30 mL) and water (1.3 mL) at 0° C. was treated dropwisewith acetyl chloride (23.0 mL, 32.4 mmol). The reaction mixture wasstirred at 0° C. for 1 h and then at room temperature for 18 h. Afterthis time, the mixture was concentrated under reduced pressure, and theresidue was dissolved in ethyl acetate, washed with water and brine,dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide (S)-2-acetoxy-2-phenylacetic acid (22.0 g, 97%): ¹HNMR (300 MHz, CDCl₃) δ 7.50-7.45 (m, 2H), 7.42-7.37 (m, 3H), 5.94 (s,1H), 2.20 (s, 3H), CO₂H proton not observed.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl 2-acetoxy-2-phenylacetate

A mixture of (S)-2-acetoxy-2-phenylacetic acid (6.50 g, 31.0 mmol) andN-hydroxysuccinimide (4.00 g, 34.8 mmol) in tetrahydrofuran (150 mL) at0° C. was added N,N′-dicyclohexylcarbodiimide (7.00 g, 33.9 mmol). Theice bath was removed, and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (100 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide (S)-2,5-dioxopyrrolidin-1-yl2-acetoxy-2-phenylacetate (10.0 g) that was used without purification:¹H NMR (300 MHz, CDCl₃) δ 7.57-7.52 (m, 2H), 7.46-7.43 (m, 3H), 6.33 (s,1H), 2.80 (s, 4H), 2.20 (s, 3H).

Preparation of (S)-2-((S)-2-Acetoxy-2-phenylacetoxy)propanoic acid

A mixture of (S)-2,5-dioxopyrrolidin-1-yl 2-acetoxy-2-phenylacetate(3.40 g, 11.6 mmol), (S)-2-hydroxypropanoic acid (1.30 g, 14.4 mmol),pyridine (1.1 mL, 13.6 mmol), and 4-dimethylaminopyridine (100 mg, 0.8mmol) in tetrahydrofuran (50 mL) was stirred at reflux for 18 h. Afterthis time, the mixture was cooled to room temperature, partiallyconcentrated under reduced pressure, diluted with ethyl acetate, andwashed with 10% citric acid. The organic layer was extracted withsaturated sodium bicarbonate. The aqueous extract was carefully treatedwith 2 N hydrochloric acid until acidic by pH paper analysis, and thenextracted with ethyl acetate. The organic extracts were dried oversodium carbonate, filtered and concentrated. The residue was purified byreversed phase column chromatography (150 g C18 column, 5-100%acetonitrile/water) to provide(S)-2-((S)-2-acetoxy-2-phenylacetoxy)propanoic acid (1.15 g, 37%): ESIMS m/z 531 [2×(C₁₃H₁₄O₆)−H]⁻.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-((S)-2-acetoxy-2-phenylacetoxy)propanoate

A mixture of (S)-2-((S)-2-acetoxy-2-phenylacetoxy)propanoic acid (1.15g, 4.32 mmol) and N-hydroxysuccinimide (545 mg, 4.74 mmol) intetrahydrofuran (20 mL) was treated with N,N′-dicyclohexylcarbodiimide(975 mg, 4.74 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (20 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide (S)-2,5-dioxopyrrolidin-1-yl2-((S)-2-acetoxy-2-phenylacetoxy)propanoate (1.64 g) that was usedwithout purification: ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.46 (m, 2H),7.42-7.35 (m, 3H), 5.99 (s, 1H), 5.49 (q, J=7.1 Hz, 1H), 2.79 (s, 4H),2.19 (s, 3H), 1.68 (d, J=7.1 Hz, 3H).

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-acetoxy-2-phenylacetoxy)propanoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (400 mg, 1.00 mmol) in tetrahydrofuran (8 mL) was cooled to−10° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.1 mL, 1.1 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to −10° C. and(S)-2,5-dioxopyrrolidin-1-yl 2-((S)-2-acetoxy-2-phenylacetoxy)propanoate(400 mg, 1.1 mmol) was added in one portion. The mixture was stirred at−10° C. to ambient temperature over 45 min. After this time, thereaction mixture was cooled in an ice bath, treated with saturatedaqueous ammonium chloride, and extracted with ethyl acetate. Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by reversephase column chromatography (50 g C18 column, 5-100% acetonitrile/water)to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-acetoxy-2-phenylacetoxy)propanoate (257 mg, 40%): ESI MS m/z650 [C₃₅H₃NO₁₁+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-acetoxy-2-phenylacetoxy)propanoate trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-acetoxy-2-phenylacetoxy)propanoate (250 mg, 0.38 mmol) inmethylene chloride (6 mL) was treated with trifluoroacetic acid (2 mL)and stirred at ambient temperature for 2 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas purified by reversed phase column chromatography (50 g C18 column,5-30% acetonitrile/water, with 0.1% trifluoracetic acid) and freezedried to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((S)-2-acetoxy-2-phenylacetoxy)propanoate trifluoroacetic acid salt(95 mg, 35% over two steps) as a fluffy white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 9.30 (br s, 1H), 9.16 (br s, 1H), 7.53-7.49 (m, 2H),7.42-7.39 (m, 3H), 6.68 (d, J=8.2 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 6.25(s, 1H), 6.06 (s, 1H), 5.46 (dd, J=5.9, 2.0 Hz, 1H), 5.26 (q, J=7.1 Hz,1H), 4.79 (s, 1H), 6.61 (d, J=6.1 Hz, 1H), 3.36 (d, J=20.0 Hz, 1H),3.12-3.01 (m, 2H), 2.87-2.82 (m, 3H), 2.69-2.57 (m, 1H), 2.41 (dd,J=13.2, 4.7 Hz, 1H), 2.26 (dd, J=18.0, 6.2 Hz, 1H), 2.13 (s, 3H), 2.03(d, J=18.0 Hz, 1H), 1.59 (d, J=10.9 Hz, 1H), 1.50 (d, J=7.1 Hz, 3H); ESIMS m/z 550 [C₃₀H₃₁NO₉+H]⁺; HPLC (Method A) 97.4% (AUC), t_(R)=9.46 min.

Preparation of(S)-4-((1-(tert-Butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoic acid

A solution of (S)-tert-butyl 2-hydroxypropanoate (3.40 g, 23.3 mmol) intetrahydrofuran (50 mL) was cooled in an ice bath and treated with a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (30.3mL, 30.3 mmol) under a nitrogen atmosphere. After 10 min, the mixturewas treated dropwise with a solution of succinic anhydride (2.80 g, 27.9mmol) in tetrahydrofuran (25 mL) and stirred at 0° C. for 45 min. Afterthis time, the reaction mixture was poured into saturated aqueousammonium chloride and extracted with ethyl acetate. The combinedorganics were dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude residue was purified by columnchromatography (silica gel, 0-20% methanol/methylene chloride) andtriturated with ether, filtered, and concentrated under reduced pressureto provide (S)-4-((1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (0.600 g, 10%) as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ12.18 (br s, 1H), 4.81 (q, J=7.2 Hz, 1H), 2.51-2.49 (m, 4H, partiallyobscured by solvent peak), 1.40 (s, 9H), 1.36 (d, J=7.2 Hz, 3H).

Preparation of (S)-1-(tert-Butoxy)-1-oxopropan-2-yl(2,5-dioxopyrrolidin-1-yl) succinate

A solution of(S)-4-((1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoic acid (0.700mg, 2.84 mmol) in tetrahydrofuran (12 mL) was treated withN-hydroxysuccinimide (0.459 mg, 3.98 mmol) andN,N′-dicyclohexylcarbodiimide (0.822 mg, 3.98 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure. The crude residue was trituratedwith diethyl ether. The resulting solid was isolated by filtration andwashed with diethyl ether. The combined filtrate and washings wereconcentrated under reduced pressure to provide(S)-1-(tert-butoxy)-1-oxopropan-2-yl (2,5-dioxopyrrolidin-1-yl)succinate (0.900 g, 92%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.00(q, J=7.2 Hz, 1H), 2.99-2.96 (m, 2H), 2.85-2.80 (m, 6H), 1.48-1.45 (m,12H).

Preparation of (S)-1-(tert-Butoxy)-1-oxopropan-2-yl((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (12 mL) was cooled to0° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.46 mL, 1.46 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 25 min andthen at ambient temperature for 25 min. The mixture was re-cooled to−78° C., and (S)-1-(tert-butoxy)-1-oxopropan-2-yl(2,5-dioxopyrrolidin-1-yl) succinate (500 mg, 1.46 mmol) was added. Themixture was allowed to warm to 0° C. over 2 h. After this time, themixture was treated with saturated aqueous ammonium chloride andextracted with ethyl acetate. The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (150 g C18column, 5-100% acetonitrile/water) to provide(S)-1-(tert-butoxy)-1-oxopropan-2-yl((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)succinate (356 mg, 45%): ESI MS m/z 630 [C₃₃H₄₃NO₁₁+H]⁺.

Preparation of(S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt

A solution of (S)-1-(tert-butoxy)-1-oxopropan-2-yl((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)succinate (350 mg, 0.56 mmol) in methylene chloride (6 mL) was treatedwith trifluoroacetic acid (3 mL) and stirred at ambient temperature for2 h. After this time, the reaction mixture was concentrated underreduced pressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 5-30% acetonitrile/water, with 0.1%trifluoracetic acid) and freeze dried to provide(S)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt (186 mg, 52% over two steps) as a fluffywhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 13.05 (br s, 1H), 9.33 (br s,1H), 9.18 (br s, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.62 (d, J=8.2 Hz, 1H),6.28 (s, 1H), 5.52 (dd, J=5.7, 1.8 Hz, 1H), 4.98-4.89 (m, 2H), 3.63 (d,J=6.2 Hz, 1H), 3.37 (d, J=19.9 Hz, 1H), 3.13-3.00 (m, 2H), 3.84 (s, 3H),2.76-2.55 (m, 5H), 2.43 (dd, J=13.2, 4.6 Hz, 1H), 2.27 (dd, J=17.9, 6.1Hz, 1H), 2.05 (d, J=16.2 Hz, 1H), 1.62 (d, J=11.0 Hz, 1H), 1.40 (d,J=7.1 Hz, 3H); ESI MS m/z 474 [C₂₄H₂₇NO₉+H]⁺; HPLC (Method A) 96.8%(AUC), t_(R)=7.28 min.

Preparation of(S)-4-((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)1-tert-butyl 2-((tert-butoxycarbonyl)amino)succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (870 g, 2.17 mmol) in tetrahydrofuran (15 mL) was cooled to 0°C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (2.37 mL, 2.37 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 25 min andthen at ambient temperature for 25 min. The mixture was re-cooled to−78° C. and (S)-1-tert-butyl 4-(2,5-dioxopyrrolidin-1-yl)2-((tert-butoxycarbonyl)amino)succinate (870 mg, 2.25 mmol) was added.The mixture was allowed to warm to 0° C. over 2 h. After this time, themixture was treated with saturated aqueous ammonium chloride, andextracted with ethyl acetate. The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (150 g C18column, 5-100% acetonitrile/water) to provide(S)-4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)1-tert-butyl 2-((tert-butoxycarbonyl)amino)succinate (610 mg, 38%): ESIMS m/z 673 [C₃₅H₄₈N₂O₁₁+H]⁺.

Preparation of (S)-1-tert-Butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-aminosuccinate trifluoroacetic acid salt

A solution(S)-4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)1-tert-butyl 2-((tert-butoxycarbonyl)amino)succinate (610 mg, 0.91 mmol)in methylene chloride (7 mL) was treated with trifluoroacetic acid (1mL) and stirred at ambient temperature for 2 h. After this time, thereaction mixture was concentrated under reduced pressure to obtain(S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-aminosuccinate trifluoroacetic acid salt (600 mg) that was used in thenext step without purification: ESI MS m/z 473 [C₂₅H₃₂N₂O₇+H]⁺.

Preparation of (S)-1-tert-Butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((S)-2-acetoxypropanamido)succinate

A mixture of (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-aminosuccinate trifluoroacetic acid salt (600 mg) and(S)-2,5-dioxopyrrolidin-1-yl 2-acetoxypropanoate (230 mg, 1.00 mmol) intetrahydrofuran (8 mL) was treated with N,N-diisopropylethylamine (0.6mL, 3.44 mmol). The reaction mixture was stirred at room temperature for1 h. After this time, the mixture was diluted with ethyl acetate andwashed with water and brine. The organic extracts were dried over sodiumsulfate, filtered, and concentrated. The residue was purified byreversed phase column chromatography (15.5 g C18 column, 5-100%acetonitrile/water) to provide (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((S)-2-acetoxypropanamido)succinate (135 mg, 26%): ESI MS m/z 587[C₃₀H₃₈N₂O₁₀+H]⁺.

Preparation of(S)-2-((S)-2-Acetoxypropanamido)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((S)-2-acetoxypropanamido)succinate (135 mg, 0.230 mmol) in methylenechloride (5 mL) was treated with trifluoroacetic acid (1.5 mL) andstirred at room temperature for 3 h. After this time, the mixture wasconcentrated. The residue was purified by reversed phase columnchromatography (15.5 g C18 column, 3-25% acetonitrile/water, with 0.1%trifluoracetic acid) and freeze dried to provide(S)-2-((S)-2-acetoxypropanamido)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (92 mg, 62%): ¹H NMR (300 MHz, DMSO-d₆) δ9.28 (br s, 1H), 9.16 (br s, 1H), 8.45 (d, J=8.3 Hz, 1H), 6.68 (d, J=8.2Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 6.24 (s, 1H), 5.52 (dd, J=5.9, 1.9 Hz,1H), 4.98 (q, J=6.8 Hz, 1H), 4.93 (s, 1H), 4.65 (q, J=6.9 Hz, 1H), 3.61(d, J=6.3 Hz, 1H), 3.11-2.93 (m, 3H), 2.91-2.74 (m, 4H), 2.70-2.58 (m,1H), 2.48-2.39 (m, 1H), 2.28 (dd, J=17.7, 6.2 Hz, 1H), 2.06 (d, J=14.0Hz, 1H), 1.62 (d, J=11.0 Hz, 1H), 1.33 (d, J=6.9 Hz, 3H), CO₂H protonnot observed, four protons obscured by solvent peaks; ESI MS m/z 531[C₂₆H₃₀N₂O₁₀+H]⁺; HPLC (Method A) 95.2% (AUC), t_(R)=7.00 min.

Preparation of(2S,2′S)—O′⁴,O⁴-((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-4a,7-diyl) 1-di-tert-butylbis(2-((tert butoxycarbonyl)amino)succinate)

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (1.60 g, 3.99 mmol) in tetrahydrofuran (25 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (8.5 mL, 8.5 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to 0° C., and (S)-1-tert-butyl4-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)amino)succinate(3.10 g, 8.0 mmol) was added in one portion. The mixture was stirred at0° C. for 30 min and then at ambient temperature for 30 min. After thistime, the reaction mixture was cooled in an ice bath, treated withsaturated aqueous ammonium chloride, and extracted with ethyl acetate.The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by reversephase column chromatography (150 g C18 column, 5-100%acetonitrile/water) to provide(2S,2′S)—O′⁴,O⁴-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)1-di-tert-butyl bis(2-((tert-butoxycarbonyl)amino)succinate) (1.95 g,52%): ESI MS m/z 944 [C₄₈H₆₉N₃O₁₆+H]⁺.

Preparation of (2S,2′S)-1-d -tert-ButylO′⁴,O′-((4R,4aS,7aR,12bS)-9-Hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(2-aminosuccinate) trifluoroacetic acid salt

A solution of(2S,2′S)—O′⁴,O⁴-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)1-di-tert-butyl bis(2-((tert-butoxycarbonyl)amino)succinate) (1.22 g,1.29 mmol) in methylene chloride (15 mL) was treated withtrifluoroacetic acid (2.5 mL) and stirred at ambient temperature for 2.5h. After this time, the reaction mixture was concentrated under reducedpressure to provide (2S,2′S)-1-di-tert-butylO′⁴,O⁴-((4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(2-aminosuccinate) trifluoroacetic acid salt (900 mg) that was usedwithout purification: ESI MS m/z 644 [C₃₃H₄₅N₃O₁₀+H]⁺.

Preparation of (S,2S,2′S)-1-Di-tert-butylO′⁴,O′⁴-((4R,4aS,7aR,12bS)-9-Hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)succinate)

A mixture of (2S,2′S)-1-di-tert-butylO′⁴,O⁴-((4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(2-aminosuccinate) trifluoroacetic acid salt (590 mg, 0.60 mmol) and(S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (560 mg, 1.59 mmol) intetrahydrofuran (7 mL) was treated with N,N-diisopropylethylamine (0.90mL, 5.2 mmol) and stirred at room temperature for 2.5 h. After thistime, the reaction mixture was diluted with ethyl acetate and washedwith water and brine. The organic extracts were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by reversed phase column chromatography (50 g C18 column,5-100% acetonitrile/water) to provide (S,2S,2′S)-1-di-tert-butylO′⁴,O⁴-((4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)succinate)(100 mg, 15%): ESI MS m/z 1112 [C₅₉H₇₃N₃O₁₈+H]⁺.

Preparation of(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-Hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-((S)-2-hydroxy-2-phenylacetamido)-4-oxobutanoicacid) trifluoroacetic acid salt

A solution of (S,2S,2′S)-1-di-tert-butylO′⁴,O⁴-((4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)succinate)(100 mg, 0.09 mmol) in methylene chloride (5 mL) was treated withtrifluoroacetic acid (1.5 mL) and stirred at ambient temperature for 4h. After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (15.5 g C18 column, 3-30% acetonitrile/water, with 0.1%trifluoracetic acid) and freeze dried to provide(S,2S,2′S)-4,4′-(((4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(2-((S)-2-hydroxy-2-phenylacetamido)-4-oxobutanoicacid) trifluoroacetic acid salt (18 mg, 22%): ¹H NMR (300 MHz, DMSO-d₆,Mixture of diastereomers) δ 9.35 (s, 1H), 8.48 (d, J=8.4 Hz, 0.18H),8.43 (d, J=8.3 Hz, 0.82H), 8.25 (d, J=7.2 Hz, 1H), 7.44-7.17 (m, 10H),6.69 (d, J=8.2 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 6.41-6.30 (m, 2H), 5.34(d, J=5.9 Hz, 0.18H), 5.25 (d, J=4.5 Hz, 0.82H), 5.00-4.89 (m, 3H),4.74-4.47 (m, 3H), 3.18-2.94 (m, 4H), 2.93-2.67 (m, 8H), 2.45-2.43 (m,2H), 2.09-1.98 (m, 1H), 1.73-1.61 (m, 1H), CO₂H protons not observed;ESI MS m/z 800 [C₄₁H₄₁N₃O₁₄+H]⁺; HPLC (Method A) 94.4% (AUC), t_(R)=8.52min.

Preparation of (R)-2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid

A solution of (R)-malic acid (4.50 g, 33.6 mmol), 2-methoxyprop-1-ene(9.68 g, 134 mmol) and pyridinium p-toluenesulfonate (844 mg, 3.36 mmol)in acetone (50 mL) was stirred at 35° C. for 16 h. After this time,water (200 mL) was added, and the aqueous solution was extracted withethyl acetate (2×200 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas recrystallized from ethyl acetate/heptane to provide(R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (2.92 g, 50%) asan off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 4.72 (dd, J=6.6, 3.9 Hz,1H), 3.01 (dd, J=17.4, 3.9 Hz, 1H), 2.86 (dd, J=17.4, 6.6 Hz, 1H), 1.63(s, 3H), 1.58 (s, 3H), CO₂H proton not observed.

Preparation of (R)-tert-Butyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate

A solution of (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid(2.92 g, 16.8 mmol) and tert-butanol (1.86 g, 25.2 mmol) in methylenechloride (40 mL) was treated with N,N′-dicyclohexylcarbodiimide (4.16 g,20.2 mmol) and 4-(dimethylamino)pyridine (616 mg, 5.04 mmol) and stirredat room temperature under a nitrogen atmosphere for 4 h. After thistime, the reaction mixture was filtered to remove the soliddicyclohexylurea byproduct. The solid was washed with diethyl ether (100mL), and the combined filtrate and washings were concentrated underreduced pressure. The crude residue was purified by columnchromatography (80 g silica gel column, 0-30% ethyl acetate/heptane) toprovide (R)-tert-butyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate(3.19 g, 82%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 4.66 (dd,J=6.0, 3.9 Hz, 1H), 2.84 (dd, J=17.1, 4.2 Hz, 1H), 2.72 (dd, J=16.8, 6.3Hz, 1H), 1.63 (s, 3H), 1.56 (s, 3H), 1.47 (s, 9H).

Preparation of (R)-4-(tert-Butoxy)-2-hydroxy-4-oxobutanoic acid

A solution of (R)-tert-butyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (3.19 g, 13.9 mmol) inacetic acid (21 mL) and water (9 mL) was stirred at 60° C. for 4 h.After this time, the solvent was removed under reduced pressure. Theresidue was dried under vacuum to provide(R)-4-(tert-butoxy)-2-hydroxy-4-oxobutanoic acid (2.81 g) as a colorlessoil: ¹H NMR (300 MHz, DMSO-d₆) δ 4.48 (dd, J=5.7, 5.4 Hz, 1H), 2.83 (m,2H), 1.48 (m, 9H), CO₂H and OH protons not observed.

Preparation of (R)-2-Acetoxy-4-(tert-butoxy)-4-oxobutanoic acid

(R)-4-(tert-Butoxy)-2-hydroxy-4-oxobutanoic acid (2.81 g, 14.8 mmol),acetyl chloride (1.28 g, 16.3 mmol), N,N-diisopropylethylamine (5.74 g,44.4 mmol), and methylene chloride (150 mL) were combined at 0° C. andthen stirred at room temperature under a nitrogen atmosphere for 4 h.After this time, 10% aqueous citric acid (100 mL) was added. The organiclayer was separated and extracted with methylene chloride (2×100 mL).The combined organics were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(R)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoic acid (3.44 g) as a blackoil, which was used without purification.

Preparation of (R)-Di-tert-butyl 2-acetoxysuccinate

A solution of (R)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoic acid (3.44 g,14.8 mmol) and tert-butanol (2.41 g, 32.6 mmol) in methylene chloride(70 mL) was treated with N,N′-dicyclohexylcarbodiimide (3.69 g, 19.2mmol) and 4-(dimethylamino)pyridine (597 mg, 4.88 mmol) and stirred atroom temperature under a nitrogen atmosphere for 16 h. After this time,the reaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether (100 mL), and thecombined filtrate and washings were concentrated under reduced pressure.The crude residue was purified by column chromatography (80 g silica gelcolumn, 0-30% ethyl acetate/heptane) to provide (R)-di-tert-butyl2-acetoxysuccinate (1.70 g, 40%) as a colorless oil: ¹H NMR (300 MHz,CDCl₃) δ 5.30 (dd, J=7.5, 5.4 Hz, 1H), 2.75 (m, 2H), 2.12 (s, 3H), 1.46(s, 18H).

Preparation of (R)-Di-tert-butyl 2-hydroxysuccinate

(R)-Di-tert-butyl 2-acetoxysuccinate (1.70 g, 5.90 mmol), potassiumcarbonate (2.44 g, 17.7 mmol), methanol (90 mL) and water (15 mL) werecombined and stirred at 0° C. for 3 h. After this time, water (200 mL)was added, and the aqueous solution was extracted with methylenechloride (2×200 mL). The combined organics were washed with brine (50mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide (R)-di-tert-butyl 2-hydroxysuccinate (1.16 g, 80%)as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 4.30 (dd, J=10.2, 5.7 Hz,1H), 3.19 (d, J=5.4 Hz, 1H), 2.75-2.66 (m, 2H), 1.47 (s, 9H), 1.45 (s,9H).

Preparation of(R)-4-((1,4-Di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoic acid

(R)-Di-tert-butyl 2-hydroxysuccinate (1.16 g, 4.71 mmol),dihydrofuran-2,5-dione (1.41 g, 14.1 mmol), N,N-diisopropylethylamine(1.82 g, 14.1 mmol), and methylene chloride (30 mL) were combined andstirred at room temperature under a nitrogen atmosphere for 16 h. Afterthis time, 10% aqueous citric acid (100 mL) was added. The organic layerwas separated and extracted with methylene chloride (2×50 mL). Thecombined organics were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(R)-4-((1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoic acid(2.05 g) as a brown oil: ¹H NMR (300 MHz, CDCl₃) δ 5.32 (dd, J=7.5, 5.1Hz, 1H), 2.77-2.66 (m, 6H), 1.45 (s, 18H), CO₂H proton not observed.

Preparation of (R)-Di-tert-butyl2-((4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanoyl)oxy)succinate

A solution of(R)-4-((1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoic acid(2.05 g, 5.92 mmol) in tetrahydrofuran (60 mL) was treated withN-hydroxysuccinimide (681 mg, 5.92 mmol) andN,N′-dicyclohexylcarbodiimide (1.22 g, 5.92 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (R)-di-tert-butyl2-((4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanoyl)oxy)succinate (2.75g) as a brown oil: ¹H NMR (300 MHz, CDCl₃) δ 5.34 (dd, J=6.9, 5.7 Hz,1H), 3.01-2.96 (m, 2H), 2.87-2.70 (m, 8H), 1.45 (s, 18H).

Preparation (R)-Di-tert-butyl2-((4-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled to −45° C. and treated dropwisewith a solution of (R)-di-tert-butyl2-((4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanoyl)oxy)succinate (608mg, 1.37 mmol) in tetrahydrofuran (5 mL). After addition was complete,the mixture was warmed to 0° C. After this time, the reaction mixturewas treated with saturated aqueous ammonium chloride (20 mL) andextracted with ethyl acetate (2×25 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (40 g silica gelcolumn, 0-20% methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide (R)-di-tert-butyl2-((4-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinate(100 mg, 11%) as a white solid: ESI MS m/z 730 [C₃₈H₅₁NO₁₃+H]⁺.

Preparation of(R)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid trifluoroacetic acid salt

A solution of (R)-di-tert-butyl2-((4-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinate(100 mg, 0.137 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(R)-2-((4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid trifluoroacetic acid salt (48 mg, 55%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 13.2 (br s, 1H), 12.6 (br s, 1H), 9.30 (s, 1H),9.17 (br s, 1H), 6.64 (q, J=8.1 Hz, 2H), 6.24 (br s, 1H), 5.53 (dd,J=6.3, 2.1 Hz, 1H), 5.22 (dd, J=7.8, 4.5 Hz, 1H), 4.95 (s, 1H),3.41-3.32 (m, 1H), 3.04 (m, 1H), 2.86-2.61 (m, 10H), 2.51-2.42 (m, 3H),2.26 (m, 1H), 2.06 (d, J=18.0 Hz, 1H), 1.62 (d, J=10.8 Hz, 1H); ESI MSm/z 518 [C₂₅H₂₇NO₁₁+H]⁺; HPLC (Method A) 95.3% (AUC), t_(R)=6.81 min.

Preparation of (S)-1-tert-Butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)succinate

A mixture of (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-aminosuccinate trifluoroacetic acid salt (490 mg, 0.70 mmol) and(S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)oxy)-2-phenylacetate (315 mg, 0.901 mmol) intetrahydrofuran (8 mL) was treated with N,N-diisopropylethylamine (0.60mL, 3.4 mmol) and stirred at room temperature for 1 h. After this time,the reaction mixture was diluted with ethyl acetate and washed withwater and brine. The organic extracts were dried over sodium sulfate,filtered, and concentrated. The residue was purified by reversed phasecolumn chromatography (50 g C18 column, 5-100% acetonitrile/water) toprovide (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)succinate (160 mg,30%): ESI MS m/z 707 [C₃₈H₄₆N₂O₁₁+H]⁺.

Preparation of(S)-4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-((S)-2-hydroxy-2-phenylacetamido)-4-oxobutanoicacid trifluoroacetic acid salt and (S)-1-tert-Butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((S)-2-hydroxy-2-phenylacetamido)succinate trifluoroacetic acid salt

A solution of (S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((S)-2-((tert-butoxycarbonyl)oxy)-2-phenylacetamido)succinate (160 mg,0.23 mmol) in methylene chloride (7 mL) was treated with trifluoroaceticacid (1 mL) and stirred at room temperature for 1.5 h. After this time,the mixture was concentrated. The residue was purified by reversed phasecolumn chromatography (15.5 g C18 column, 3-30% acetonitrile/water, with0.1% trifluoracetic acid) and freeze dried to provide(S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-((S)-2-hydroxy-2-phenylacetamido)-4-oxobutanoicacid trifluoroacetic acid salt (33 mg, 20%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 13.01 (br s, 1H), 9.30 (br s, 1H), 9.15 (br s, 1H),8.37 (d, J=8.3 Hz, 1H), 7.46-7.18 (m, 5H), 6.68 (d, J=8.1 Hz, 1H), 6.62(d, J=8.1 Hz, 1H), 6.38 (br s, 1H), 6.21 (s, 1H), 5.35 (d, J=4.2 Hz,1H), 4.96 (s, 1H), 4.89 (s, 1H), 4.67 (q, J=6.3 Hz, 1H), 3.64-3.58 (m,1H), 3.18-2.79 (m, 8H), 2.77-2.60 (m, 2H), 2.30-2.18 (dd, J=17.6, 6.1Hz, 1H), 2.03 (d, J=18.32 Hz, 1H), 1.62 (d, J=12.2 Hz, 1H); ESI MS m/z551 [C₂₉H₃₀N₂O₉+H]⁺; HPLC (Method A) 89.8% (AUC), t_(R)=7.45 min; and(S)-1-tert-butyl4-((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((S)-2-hydroxy-2-phenylacetamido)succinate trifluoroacetic acid salt(23 mg, 13%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (br s,1H), 9.14 (br s, 1H), 8.41 (d, J=8.1 Hz, 1H), 7.43-7.38 (m, 2H),7.34-7.24 (m, 3H), 6.68 (d, J=8.1 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.32(br s, 1H), 6.22 (s, 1H), 5.41-5.39 (m, 1H), 4.96 (s, 1H), 4.90 (s, 1H),4.61-4.52 (m, 1H), 3.63-3.59 (m, 1H), 3.12-2.95 (m, 3H), 2.88-2.78 (m,4H), 2.70-2.59 (m, 1H), 2.45-2.40 (m, 1H), 2.25 (dd, J=17.5, 6.3 Hz,1H), 2.04 (d, J=18.6 Hz, 1H), 1.62 (d, J=11.6 Hz, 1H), 1.33 (s, 9H), oneproton obscured by solvent peaks; ESI MS m/z 607 [C₃₃H₃₈N₂O₉+H]⁺; HPLC(Method A) 97.0% (AUC), t_(R)=9.05 min.

Preparation of(S)-2-(((S)-2-Acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic acid

(S)-Lactic acid (109 mg, 1.21 mmol), (S)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (400 mg, 1.21 mmol),4-(dimethylamino)pyridine (15 mg, 0.121 mmol), pyridine (115 mg, 1.45mmol) and tetrahydrofuran (8 mL) were combined and heated at 60° C.under a nitrogen atmosphere for 24 h. After this time, the solvent wasremoved under reduced pressure, and the residue was partitioned betweenethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer wasseparated and extracted with saturated aqueous sodium bicarbonate (20ml). The aqueous phase was collected and acidified to pH=3 with 6 Nhydrochloric acid, and the mixture was extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(S)-2-(((S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic acid(247 mg, 67%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.47 (m,1H), 5.21 (m, 1H), 2.95-2.77 (m, 2H), 2.13 (s, 3H), 1.56 (d, J=6.9 Hz,3H), 1.45 (s, 9H), CO₂H proton not observed.

Preparation of (S)-4-tert-Butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate

A solution of(S)-2-(((S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic acid(247 mg, 0.812 mmol) in tetrahydrofuran (10 mL) was treated withN-hydroxysuccinimide (103 mg, 0.893 mmol) andN,N′-dicyclohexylcarbodiimide (184 mg, 0.893 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-4-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate (384 mg) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ5.38-5.45 (m, 2H), 2.97-2.81 (m, 6H), 2.12 (s, 3H), 1.71 (q, J=6.9 Hz,3H), 1.46 (s, 9H).

Preparation of(S)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)4-tert-butyl 2-acetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (349 mg, 0.870 mmol) in tetrahydrofuran (8 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.0 mL, 1.0 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-4-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate (384 mg, 0.957 mmol) in tetrahydrofuran (5 mL). Afteraddition was complete, the mixture was warmed to 0° C. After this time,the reaction mixture was treated with saturated aqueous ammoniumchloride (20 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (40 g silica gel column, 0-20% methanol/methylenechloride, then 50 g C18 column, 10-100% acetonitrile/water) to provide(S)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)4-tert-butyl 2-acetoxysuccinate (182 mg, 30%) as a white solid: ESI MSm/z 688 [C₃₅H₄₅NO₁₃+H]⁺.

Preparation of(S)-3-Acetoxy-4-((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid

A solution of(S)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)4-tert-butyl 2-acetoxysuccinate (182 mg, 0.265 mmol) in methylenechloride (3 mL) was treated with trifluoroacetic acid (3 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 1 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 0-100% acetonitrile/water with 0.1% trifluoroacetic acid) andfreeze dried to provide(S)-3-acetoxy-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (84.2 mg, 60%) as a fluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ6.55 (apparent q, J=8.1 Hz, 2H), 5.56 (dd, J=5.7, 2.4 Hz, 1H), 5.35 (dd,J=9.0, 3.6 Hz, 1H), 5.23 (q, J=8.1 Hz, 1H), 3.09 (d, J=18.6 Hz, 1H),2.94-2.72 (m, 3H), 2.60 (dd, J=18.6, 6.3 Hz, 1H), 2.51-2.44 (m, 4H),2.35 (s, 3H), 2.27 (m, 1H), 2.13-2.00 (m, 6H), 1.53 (d, J=6.9 Hz, 3H),1.39 (d, J=10.8 Hz, 1H), CO₂H proton not observed; ESI MS m/z 532[C₂H₂₉NO₁₁+H]⁺; HPLC (Method A) 96.8% (AUC), t_(R)=7.73 min.

Preparation of (R)-2,5-Dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate

A solution of (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid(696 mg, 4.00 mmol) in tetrahydrofuran (40 mL) was treated withN-hydroxysuccinimide (506 mg, 4.40 mmol) andN,N′-dicyclohexylcarbodiimide (906 mg, 4.40 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (R)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (1.40 g, quantitative)as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 4.77 (dd, J=6.3, 3.6 Hz,1H), 3.28 (dd, J=17.4, 3.9 Hz, 1H), 3.10 (dd, J=17.1, 6.3 Hz, 1H), 2.85(s, 4H), 1.63 (s, 3H), 1.58 (s, 3H).

Preparation(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled to −45° C. and treated dropwisewith a solution of (R)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (372 mg, 1.37 mmol) intetrahydrofuran (5 mL). After addition was complete, the mixture waswarmed to 0° C. After this time, the reaction mixture was treated withsaturated aqueous ammonium chloride (20 mL) and extracted with ethylacetate (2×25 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (270 mg, 38%) as awhite solid: ESI MS m/z 558 [C₂₉H₃₅NO₁₀+H]⁺.

Preparation of(R)-4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (270 mg, 0.484 mmol)was treated with a 4.0 M solution of hydrochloric acid in 1,4-dioxane (5mL, 20.0 mmol) and water (0.2 mL). The reaction mixture was stirredunder a nitrogen atmosphere at ambient temperature for 2 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 0-100% acetonitrile/water with 0.1% trifluoroacetic acid) andfreeze dried to provide(R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoicacid trifluoroacetic acid salt (75 mg, 29%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 12.7 (s, 1H), 9.31 (s, 1H), 9.15 (br s, 1H),6.65 (apparent q, J=7.8 Hz, 2H), 6.22 (s, 1H), 5.64 (s, 1H), 5.52 (dd,J=6.0, 2.1 Hz, 1H), 4.95 (s, 1H), 4.35 (m, 1H), 3.41-3.33 (m, 2H), 3.03(m, 1H), 2.89 (d, J=4.5 Hz, 1H), 2.83 (s, 3H), 2.72-2.61 (m, 1H),2.44-2.42 (m, 1H), 2.27 (m, 1H), 2.06 (d, J=17.7 Hz, 3H), 1.63 (d,J=10.8 Hz, 1H); ESI MS m/z 418 [C₂₁H₂₃NO₈+H]⁺; HPLC (Method A) >99%(AUC), t_(R)=6.16 min.

Preparation of(S)-2-(((S)-5-(tert-Butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoicacid

(S)-Lactic acid (135 mg, 1.50 mmol), (S)-5-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)amino)pentanedioate(500 mg, 1.25 mmol), 4-(dimethylamino)pyridine (15 mg, 0.125 mmol), andpyridine (119 mg, 1.50 mmol) were combined and heated at 60° C. under anitrogen atmosphere for 48 h. After this time, the solvent was removedunder reduced pressure, and the residue was participated between ethylacetate (20 mL) and 10% aqueous citric acid. The organic layer wasseparated and extracted with saturated aqueous sodium bicarbonate (20ml). The aqueous phase was collected and acidified to pH=3 with 6 Nhydrochloric acid, and the mixture was extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(S)-2-(((S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoicacid (385 mg, 82%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.24(m, 2H), 4.32 (m, 1H), 2.40 (m, 2H), 2.20 (m, 1H), 1.99 (m, 1H), 1.56(d, J=6.9 Hz, 3H), 1.45 (s, 18H), CO₂H proton not observed.

Preparation of (S)-5-tert-Butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate

A solution of(S)-2-(((S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoicacid (385 mg, 1.03 mmol) in tetrahydrofuran (8 mL) was treated withN-hydroxysuccinimide (130 mg, 1.13 mmol) andN,N′-dicyclohexylcarbodiimide (233 mg, 1.13 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-5-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (542 mg) as a white solidthat was used without purification.

Preparation of(S)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)5-tert-butyl 2-((tert-butoxycarbonyl)amino)pentanedioate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-5-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (647 mg, 1.37 mmol) intetrahydrofuran (5 mL). After addition was complete, the mixture waswarmed to 0° C. After this time, the reaction mixture was treated withsaturated aqueous ammonium chloride (20 mL) and extracted with ethylacetate (2×50 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)5-tert-butyl 2-((tert-butoxycarbonyl)amino)pentanedioate (402 mg, 42%)as a white solid: ESI MS m/z 759 [C₃₉H₅N₂O₁₃+H]⁺.

Preparation of(S)-4-Amino-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid bis(trifluoroacetic acid salt)

A solution of(S)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)5-tert-butyl 2-((tert-butoxycarbonyl)amino)pentanedioate (210 mg, 0.277mmol) in methylene chloride (3 mL) was treated with trifluoroacetic acid(3 mL) and stirred under a nitrogen atmosphere at ambient temperaturefor 1 h. After this time, the reaction mixture was concentrated underreduced pressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 0-100% acetonitrile/water with 0.1%trifluoroacetic acid) and freeze dried to provide(S)-4-amino-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid bis(trifluoroacetic acid salt) (95 mg, 46%) as a fluffy whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.3 (br s, 1H), 9.32 (br s, 1H),9.16 (br s, 1H), 8.44 (br s, 3H), 6.66 (apparent q, J=8.1 Hz, 2H), 6.25(s, 1H), 5.61 (dd, J=6.0, 2.1 Hz, 1H), 5.34 (q, J=7.2 Hz, 1H), 4.99 (s,1H), 4.23 (m, 1H), 3.62 (m, 3H), 3.08 (m, 1H), 2.84 (s, 3H), 2.63-2.26(m, 4H), 2.11-2.05 (m, 3H), 1.76 (m, 1H), 1.63-1.58 (m, 4H); ESI MS m/z503 [C₂₅H₃₀N₂O₉+H]⁺.

Preparation of(S)-2-(((S)-2-Acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-4-(tert-butoxy)-4-oxobutanoicacid

(S)-4-(tert-Butoxy)-2-hydroxy-4-oxobutanoic acid (762 mg, 4.01 mmol),(S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (1.32g, 4.01 mmol), 4-(dimethylamino)pyridine (49 mg, 0.40 mmol), pyridine(381 mg, 4.81 mmol), and tetrahydrofuran (20 mL) were combined andheated at 60° C. under a nitrogen atmosphere for 72 h. After this time,the solvent was removed under reduced pressure, and the residue waspartitioned between ethyl acetate (20 mL) and 10% aqueous citric acid.The organic layer was separated and extracted with ethyl acetate (2×20mL). The combined organics were washed with brine (50 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure toprovide(S)-2-(((S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-4-(tert-butoxy)-4-oxobutanoicacid (1.62 g) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.49-5.45 (m,2H), 2.92-2.72 (m, 4H), 2.13 (s, 3H), 1.46 (s, 18H), CO₂H proton notobserved.

Preparation of(S)-1-((S)-4-(tert-Butoxy)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1,4-dioxobutan-2-yl)4-tert-butyl 2-acetoxysuccinate

A solution of(S)-2-(((S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-4-(tert-butoxy)-4-oxobutanoicacid (1.62 g, 4.15 mmol) in tetrahydrofuran (30 mL) was treated withN-hydroxysuccinimide (477 mg, 4.15 mmol) andN,N′-dicyclohexylcarbodiimide (855 mg, 4.15 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide(S)-1-((S)-4-(tert-butoxy)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1,4-dioxobutan-2-yl)4-tert-butyl 2-acetoxysuccinate (2.01 g) as a white solid: ¹H NMR (300MHz, CDCl₃) δ 5.84 (m, 1H), 5.47 (m, 1H), 2.98-2.75 (m, 8H), 2.12 (s,3H), 1.46 (s, 9H), 1.45 (s, 9H).

Preparation of(S)-1-((S)-4-(tert-Butoxy)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)4-tert-butyl 2-acetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-1-((S)-4-(tert-butoxy)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1,4-dioxobutan-2-yl)4-tert-butyl 2-acetoxysuccinate (668 mg, 1.37 mmol) in tetrahydrofuran(5 mL). After addition was complete, the mixture was warmed to 0° C.After this time, the reaction mixture was treated with saturated aqueousammonium chloride (20 mL) and extracted with ethyl acetate (2×50 mL).The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (40 g silica gel column, 0-20% methanol/methylenechloride, then 50 g C18 column, 10-100% acetonitrile/water) to provide(S)-1-((S)-4-(tert-butoxy)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)4-tert-butyl 2-acetoxysuccinate (83 mg, 11%) as a white solid: ESI MSm/z 788 [C₄₀H₅₃NO₁₅+H]⁺.

Preparation of(S)-1-((S)-4-(tert-Butoxy)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)4-tert-butyl 2-acetoxysuccinate trifluoroacetic acid salt

A solution of(S)-1-((S)-4-(tert-butoxy)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)4-tert-butyl 2-acetoxysuccinate (80 mg, 0.102 mmol) in methylenechloride (5.0 mL) was treated with trifluoroacetic acid (0.25 mL) andstirred under a nitrogen atmosphere at ambient temperature for 30 min.After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 0-100% acetonitrile/water with 0.1%trifluoroacetic acid) and freeze dried to provide(S)-1-((S)-4-(tert-butoxy)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1,4-dioxobutan-2-yl)4-tert-butyl 2-acetoxysuccinate trifluoroacetic acid salt (22 mg, 25%)as a fluffy white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 9.14(br s, 1H), 6.65 (apparent q, J=8.1 Hz, 2H), 6.23 (s, 1H), 5.62 (dd,J=6.0, 2.4 Hz, 1H), 5.52 (dd, J=7.2, 4.5 Hz, 1H), 5.36 (dd, J=8.7, 3.9Hz, 1H), 4.92 (s, 1H), 3.62-3.31 (m, 1H), 3.11-3.01 (m, 2H), 2.97-2.63(m, 8H), 2.47-2.27 (m, 2H), 2.08-2.03 (m, 4H), 1.63 (m, 1H), 1.44 (s,9H), 1.39 (s, 9H), one proton obscured by solvent peaks; ESI MS m/z 688[C₃₅H₄₅NO₁₃+H]⁺; HPLC (Method A) 95.3% (AUC), t_(R)=11.03 min.

Preparation of(2R,3R)-2,3-Diacetoxy-4-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (110 mg, 0.27 mmol) in tetrahydrofuran (2.5 mL) at 0° C. wastreated with a 1.0 M solution of lithium bis(trimethylsilyl)amide intetrahydrofuran (0.3 mL, 0.3 mmol), and the mixture was stirred for 5min at 0° C. and 10 min at room temperature. The reaction mixture wascooled to 0° C., and (3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate(89 mg, 0.41 mmol) was added in one portion. The mixture was stirred at0° C. for 20 min and then at room temperature for 30 min. After thistime, the mixture was poured into a saturated solution of ammoniumchloride and extracted with ethyl acetate. The organic extract was driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(2R,3R)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid (100 mg): ESI MS m/z 618 [C₃₀H₃₅NO₁₃+H]⁺.

Preparation of(2R,3R)-2,3-Diacetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(2R,3R)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid (100 mg) in methylene chloride (4 mL) was treated withtrifluoroacetic acid (0.8 mL) and stirred at ambient temperature for 1.5h. After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 3-25% acetonitrile/water, with 0.1%trifluoracetic acid) and freeze dried to provide(2R,3R)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (28 mg, 20% over two steps): ¹H NMR (300MHz, DMSO-d₆) δ 9.34 (s, 1H), 9.15 (br s, 1H), 6.68 (d, J=8.1 Hz, 1H),6.63 (d, J=8.1 Hz, 1H), 6.29 (br s, 1H), 5.77 (d, J=2.8 Hz, 1H), 5.68(d, J=2.8 Hz, 1H), 5.52 (d, J=4.1 Hz, 1H), 4.83 (s, 1H), 3.62 (d, J=6.0Hz, 1H), 3.12-3.01 (m, 3H), 2.83 (s, 3H), 2.70-2.56 (m, 1H), 2.46-2.39(m, 1H), 2.28 (dd, J=17.7, 6.0 Hz, 1H), 2.19 (s, 3H), 2.15 (s, 3H), 2.07(d, J=16.4 Hz, 1H), 1.62 (d, J=11.2 Hz, 1H), CO₂H proton not observed;ESI MS m/z 518 [C₂₅H₂₇NO₁₁+H]⁺; HPLC (Method A) 83.9% (AUC), t_(R)=6.99min.

Preparation of (S)-tert-Butyl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate

A mixture of (S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (2.0 g, 7.3 mmol),(S)-tert-butyl 2-hydroxy-2-phenylacetate (1.5 g, 7.3 mmol), pyridine(0.6 mL, 7.4 mmol), and 4-dimethylaminopyridine (80 mg, 0.65 mmol) intetrahydrofuran (30 mL) was stirred at reflux for 36 h. After this time,the mixture was cooled to room temperature, concentrated under reducedpressure, and purified by column chromatography (80 g silica gel column,5-80% ethyl acetate/heptane) to provide (S)-tert-butyl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate(1.18, 44%) as a 7:3 mixture of epimers: ¹H NMR (300 MHz, CDCl₃) δ7.47-7.41 (m, 2H), 7.41-7.36 (m, 3H), 5.87 (s, 0.3H), 5.82 (s, 0.7H),4.78-4.73 (m, 1H), 3.17-3.03 (m, 1H), 2.99-2.87 (m, 1H), 1.55 (s, 6H),1.40 (s, 2.7H), 1.39 (s, 6.3H).

Preparation of(S)-4-((S)-2-(tert-Butoxy)-2-oxo-1-phenylethoxy)-2-hydroxy-4-oxobutanoicacid

A mixture of (S)-tert-butyl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)-2-phenylacetate(1.15 g, 3.16 mmol) in acetic acid (13 mL) and water (8 mL) was stirredat 60° C. for 4 h. After this time the mixture was concentrated todryness to provide(S)-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-2-hydroxy-4-oxobutanoicacid (1.09 g, quantitative, 7:3 mixture of epimers): ESI MS m/z 647[2×(C₁₆H₂₀O₇)−H]⁻.

Preparation of(S)-2-Acetoxy-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid

A solution of(S)-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-2-hydroxy-4-oxobutanoicacid (1.09 g, 3.36 mmol) and N,N-diisopropylethylamine (1.7 mL, 9.8mmol) in methylene chloride (30 mL) at 0° C. was treated dropwise withacetyl chloride (0.29 mL, 4.1 mmol). The reaction mixture was stirred at0° C. for 10 min and then at room temperature for 40 min. After thistime, the mixture was diluted with methylene chloride and washed withsaturated ammonium chloride and brine. The organic layer was dried oversodium sulfate, filtered, and concentrated to provide(S)-2-acetoxy-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (1.15 g, 92%): ESI MS m/z 384 [C₁₈H₂₂O₈+NH₄]⁺.

Preparation of (S)-4-((S)-2-(tert-Butoxy)-2-oxo-1-phenylethyl)1-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate

A mixture of(S)-2-acetoxy-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (1.1 g, 3.0 mmol) and N-hydroxysuccinimide (380 mg, 3.30 mmol) intetrahydrofuran (15 mL) was treated with N,N′-dicyclohexylcarbodiimide(680 mg, 3.30 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (20 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide(S)-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)1-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (1.4 g) that was usedwithout purification.

Preparation of (S)-4-((S)-2-(tert-Butoxy)-2-oxo-1-phenylethyl)1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (420 mg, 1.05 mmol) in tetrahydrofuran (8 mL) was cooled to 0°C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.1 mL, 1.1 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to 0° C., and(S)-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)1-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (500 mg, 1.08 mmol) wasadded. The mixture was stirred at 0° C. for 1 h. After this time, themixture was treated with saturated aqueous ammonium chloride andextracted with ethyl acetate. The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 5-100% acetonitrile/water) to provide(S)-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate (140 mg, 18%, 7:3 mixture of epimers): ESI MS m/z 750[C₄₀H₄₇NO₁₃+H]⁺.

Preparation of(S)-2-(((S)-3-Acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt

A solution of (S)-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate (140 mg, 0.18 mmol) in methylene chloride (6 mL) wastreated with trifluoroacetic acid (1 mL) and stirred at ambienttemperature for 4 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (15.5 g C18 column, 3-30%acetonitrile/water, with 0.1% trifluoracetic acid) and freeze dried toprovide(S)-2-(((S)-3-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt (43 mg, 32%) as a 7:3 mixture of epimers:¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.15 (s, 1H), 7.51-7.39 (m,5H), 6.68 (d, J=8.1 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.27 (s, 1H),5.92-5.87 (m, 1H), 5.61-5.47 (m, 2H), 4.94 (m, 0.7H), 4.90 (s, 0.3H),3.62 (d, J=6.4 Hz, 1H), 3.24-3.01 (m, 5H), 2.83 (s, 3H), 2.71-2.56 (m,1H), 2.48-2.36 (m, 1H), 2.33-2.21 (m, 1H), 2.12-2.02 (m, 4H), 1.66-1.57(m, 1H), CO₂H proton not observed; ESI MS m/z 594 [C₃₁H₃₁NO₁₁+H]⁺; HPLC(Method A) 91.0% (AUC), t_(R)=8.91 min.

Preparation of (S)-4-Benzyl 1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)2-hydroxysuccinate

A solution of (S)-tert-butyl 2-hydroxypropanoate (1.11 g, 7.61 mmol) intetrahydrofuran (15 mL) was cooled in an ice bath and treated dropwisewith a 1.0 M solution of lithium bis(trimethylsilyl)amide intetrahydrofuran (7.6 mL, 7.6 mmol). After addition was complete, themixture was stirred at ambient temperature for 15 min. The mixture wasre-cooled in the ice bath and treated dropwise with a solution of(S)-benzyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (2.01 g, 7.61mmol) in tetrahydrofuran (10 mL). After addition was complete, themixture was stirred at 0° C. for 4 h. After this time, the reactionmixture was treated with saturated aqueous ammonium chloride (10 mL) andextracted with ethyl acetate (2×25 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (silica gel,0-30% ethyl acetate/heptanes) to provide (S)-4-benzyl1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl) 2-hydroxysuccinate (0.89, 33%)as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.38-7.35 (m, 5H), 5.17(d, J=1.0 Hz, 1H), 5.05 (dd, J=14.1, 8.4 Hz, 1H), 4.69-4.53 (m, 1H),3.15 (dd, J=18.0, 6.0 Hz, 1H), 3.02 (dd, J=15.9, 3.9 Hz, 1H), 2.90-2.80(m, 1H), 1.46 (d, J=8.1 Hz, 3H), 1.45 (s, 9H), OH proton not observed.

Preparation of (S)-4-Benzyl 1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate

(S)-4-Benzyl 1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl) 2-hydroxysuccinate(1.86 g, 5.28 mmol), di-tert-butyl dicarbonate (1.38 g, 6.34 mmol), andN,N-dimethylpyridin-4-amine (64 mg, 0.53 mmol) were combined and stirredin methylene chloride (60 mL) at ambient temperature for 3 h. After thistime, the mixture was concentrated under reduced pressure. The cruderesidue was purified by column chromatography (silica gel, 0-30% ethylacetate/heptanes) to provide (S)-4-benzyl1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate (1.91 g, 80%) as a colorless oil:¹H NMR (300 MHz, CDCl₃) δ 7.38-7.33 (m, 5H), 5.41 (dd, J=9.6, 3.3 Hz,1H), 5.21 (d, J=12.3 Hz, 1H), 5.13 (d, J=12.3 Hz, 1H), 5.02 (dd, J=14.1,3.6 Hz, 1H), 3.12 (dd, J=17.8, 3.6 Hz, 1H), 2.95 (dd, J=18.1, 8.1 Hz,1H), 1.49 (s, 9H), 1.45 (d, J=6.2 Hz, 3H), 1.44 (s, 9H).

Preparation of(S)-4-(((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)oxy)-3-((tert-butoxycarbonyl)oxy)-4-oxobutanoicacid

A solution of (S)-4-benzyl 1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate (0.27 g, 0.60 mmol) in ethylalcohol (5 mL) was treated with palladium on carbon (10%, 30 mg). Themixture was stirred with under a hydrogen atmosphere at ambienttemperature for 2 h. After this time, the reaction mixture was filteredand concentrated under reduced pressure to provide(S)-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-3-((tert-butoxycarbonyl)oxy)-4-oxobutanoicacid (0.22 g, 99%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.38(dd, J=9.3, 3.6 Hz, 1H), 5.05 (dd, J=14.1, 6.9 Hz, 1H), 3.13 (dd,J=17.1, 3.3 Hz, 1H), 2.95 (dd, J=17.1, 9.3 Hz, 1H), 1.50 (s, 9H), 1.47(d, J=6.2 Hz, 3H), 1.46 (s, 9H), CO₂H proton not observed.

Preparation of (S)-1-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate

(S)-4-(((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)oxy)-3-((tert-butoxycarbonyl)oxy)-4-oxobutanoicacid (0.21 g, 0.58 mmol), 1-hydroxypyrrolidine-2,5-dione (77 mg, 0.67mmol) and dicyclohexylcarbodiimide (0.13 g, 0.64 mmol) were combined andstirred in tetrahydrofuran (4 mL) at ambient temperature for 4 h. Afterthis time, the mixture was filtered and concentrated under reducedpressure to provide (S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate (0.3g, 99%) as a sticky solid: ¹H NMR (300 MHz, CDCl₃) δ 5.45 (dd, J=9.6,3.3 Hz, 1H), 5.05 (dd, J=14.1, 6.9 Hz, 1H), 3.46 (dd, J=17.1, 3.3 Hz,1H), 3.18 (dd, J=17.1, 9.3 Hz, 1H), 2.87-2.82 (m, 4H), 1.50 (s, 9H),1.47 (d, J=6.2 Hz, 3H), 1.46 (s, 9H).

Preparation of (S)-1-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (650 mg, 1.62 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.9 mL, 1.9 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate (818mg, 1.78 mmol) in tetrahydrofuran (5 mL). After addition was complete,the mixture was warmed to 0° C. After this time, the reaction mixturewas treated with saturated aqueous ammonium chloride (20 mL) andextracted with ethyl acetate (2×50 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (40 g silica gelcolumn, 0-20% methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate (235 mg, 19%) as a white solid:ESI MS m/z 746 [C₃₈H₅₁NO₁₄+H]⁺.

Preparation of(S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt

A solution of (S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate (157 mg, 0.210 mmol) in methylenechloride (4 mL) was treated with trifluoroacetic acid (3 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 2 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 0-100% acetonitrile/water with 0.1% trifluoroacetic acid) andfreeze dried to provide(S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-hydroxy-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt (54 mg, 42%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 13.1 (br s, 1H), 9.30 (s, 1H), 9.14 (br s, 1H),6.64 (apparent q, J=8.1 Hz, 2H), 6.22 (s, 1H), 5.96 (d, J=6.3 Hz, 1H),5.55 (dd, J=6.0, 1.8 Hz, 1H), 5.03-4.97 (m, 2H), 4.52 (m, 1H), 3.41-3.33(m, 1H), 3.04 (m, 1H), 2.95 (dd, J=15.9, 4.2 Hz, 1H), 2.84 (s, 3H),2.73-2.64 (m, 2H), 2.51-2.42 (m, 3H), 2.27 (m, 1H), 2.05 (d, J=17.7 Hz,1H), 1.63 (m, 1H), 1.42 (d, J=6.9 Hz, 3H); ESI MS m/z 490[C₂₄H₂₇NO₁₀+H]⁺; HPLC (Method A) 97.7% (AUC), t_(R)=6.92 min.

Preparation of(S)-3-Acetoxy-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid

A solution of (S)-2,5-dioxotetrahydrofuran-3-yl acetate (720 mg, 4.56mmol) in N,N-dimethylformamide (4 mL) at 0° C. was treated with(S)-tert-butyl 2-hydroxy-2-phenylacetate (1.10 g, 5.29 mmol) followed bypyridine (0.37 mL, 4.59 mmol), and the mixture was allowed to warm toroom temperature and stirred for 18 h. After this time, the reactionmixture was diluted with ethyl acetate and extracted with saturatedsodium bicarbonate. The aqueous layer was collected, carefully treatedwith 6 N hydrochloric acid until acidic by pH paper analysis, and thenextracted with ethyl acetate. The organic extracts were dried oversodium sulfate, filtered, and concentrated to provide(S)-3-acetoxy-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (810 mg, 49%): ESI MS m/z 750 [2×(C₁₈H₂₂O₈)+NH₄]⁺.

Preparation of (S)-1-((S)-2-(tert-Butoxy)-2-oxo-1-phenylethyl)4-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate

A mixture of(S)-3-acetoxy-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (1.03 g, 2.73 mmol) and N-hydroxysuccinimide (340 mg, 2.95 mmol) intetrahydrofuran (15 mL) was treated with N,N′-dicyclohexylcarbodiimide(610 mg, 2.95 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (20 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide(S)-1-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (1.3 g) that was usedwithout purification.

Preparation of (S)-1-((S)-2-(tert-Butoxy)-2-oxo-1-phenylethyl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (400 mg, 1.00 mmol) in tetrahydrofuran (8 mL) was cooled to 0°C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.1 mL, 1.1 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to 0° C., and(S)-1-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (500 mg, 1.09 mmol) wasadded in one portion. The mixture was stirred at 0° C. for 1 h. Afterthis time, the mixture was treated with saturated aqueous ammoniumchloride, and extracted with ethyl acetate. The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 5-100% acetonitrile/water) to provide(S)-1-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate (230 mg, 33%): ESI MS m/z 750 [C₄₀H₄₇NO₁₃+H]⁺.

Preparation of(S)-2-(((S)-2-Acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt

A solution of (S)-1-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate (225 mg, 0.300 mmol) in methylene chloride (7 mL) wastreated with trifluoroacetic acid (1 mL) and stirred at ambienttemperature for 3 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 3-30%acetonitrile/water, with 0.1% trifluoracetic acid) and freeze dried toprovide(S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt (100 mg, 45%): ¹H NMR (300 MHz, DMSO-d₆)δ 9.30 (br s, 1H), 9.15 (br s, 1H), 7.52-7.39 (m, 5H), 6.68 (d, J=8.2Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 6.23 (s, 1H), 5.97 (s, 1H), 5.57-5.47(m, 2H), 4.96 (s, 1H), 6.31 (d, J=6.0 Hz, 1H), 3.12-3.00 (m, 4H), 2.84(s, 3H), 2.71-2.49 (m, 1H), 2.50-2.40 (m, 1H), 2.34-2.21 (m, 1H),2.15-2.00 (m, 4H), 1.63 (d, J=11.8 Hz, 1H), CO₂H proton not observed;ESI MS m/z 594 [C₃₁H₃₁NO₁₁+H]⁺; HPLC (Method A) 99.5% (AUC), t_(R)=8.96min.

Preparation of(S)-2-(((S)-3-Acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic acid

A solution of (S)-1-tert-butyl 4-(2,5-dioxopyrrolidin-1-yl)2-acetoxysuccinate (1.46 g, 4.44 mmol), lactic acid (447 mg, 4.96 mmol),and 4-dimethylaminopyridine (57 mg, 0.47 mmol) in tetrahydrofuran (30mL) was treated with pyridine (0.72 g, 8.9 mmol) and heated at 50° C.under a nitrogen atmosphere for 48 h. After this time, the reactionmixture was cooled to room temperature and concentrated under reducedpressure. The residue was dissolved in ethyl acetate (50 mL) and washedwith aqueous 10% citric acid (2×25 mL) and water (25 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by column chromatography (silica gel, 0-10%methanol/methylene chloride) to(S)-2-(((S)-3-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic (455mg, 34%) as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 13.07 (br s,1H), 5.17 (dd, J=7.8, 4.8 Hz, 1H), 4.96 (q, J=6.9 Hz, 1H), 2.98-2.83 (m,2H), 2.05 (s, 3H), 1.41 (s, 9H), 1.39 (d, J=6.9 Hz, 3H).

Preparation of (S)-1-tert-Butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate

A solution of(S)-2-(((S)-3-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoic (450mg, 1.48 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (185 mg, 1.61 mmol) andN,N′-dicyclohexylcarbodiimide (338 mg, 1.64 mmol) and stirred under anitrogen atmosphere for 7 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide (S)-1-tert-butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate (703 mg, quantitative) as an off-white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 5.52 (q, J=6.9 Hz, 1H), 5.18 (dd, J=7.5, 5.1 Hz,1H), 3.05-2.91 (m, 2H), 2.82 (br s, 4H), 2.05 (s, 3H), 1.56 (d, J=6.9Hz, 3H), 1.41 (s, 9H).

Preparation of(S)-4-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)1-tert-butyl 2-acetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (387 mg, 0.964 mmol) in tetrahydrofuran (8 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.2 mL, 1.2 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-1-tert-butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-acetoxysuccinate (425 mg, 1.06 mmol) in tetrahydrofuran (4 mL). Afteraddition was complete, the mixture was warmed to 0° C. After this time,the reaction mixture was treated with saturated aqueous ammoniumchloride (20 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (40 g silica gel column, 0-20% methanol/methylenechloride, then 50 g C18 column, 10-100% acetonitrile/water) to provide(S)-4-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)1-tert-butyl 2-acetoxysuccinate (271 mg, 40%) as a white solid: ESI MSm/z 688 [C₃₅H₄₅NO₁₃+H]⁺.

Preparation of(S)-2-Acetoxy-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(S)-4-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)1-tert-butyl 2-acetoxysuccinate (170 mg, 0.247 mmol) in methylenechloride (5.0 mL) was treated with trifluoroacetic acid (3.0 mL) andstirred under a nitrogen atmosphere at ambient temperature for 2 h.After this time, the reaction mixture was concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 0-100% acetonitrile/water with 0.1%trifluoroacetic acid) and freeze dried to provide(S)-2-acetoxy-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (50 mg, 30%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 13.3 (br s, 1H), 9.29 (s, 1H), 9.15 (br s, 1H),6.65 (apparent q, J=8.1 Hz, 2H), 6.24 (s, 1H), 5.58 (dd, J=5.7, 2.1 Hz,1H), 5.27 (dd, J=8.4, 4.5 Hz, 1H), 5.18 (q, J=6.9 Hz, 1H), 4.97 (s, 1H),3.11-2.96 (m, 4H), 2.83 (d, J=3.9 Hz, 3H), 2.73-2.41 (m, 4H), 2.29 (m,1H), 2.09-2.04 (m, 4H), 1.63 (m, 1H), 1.52 (d, J=7.2 Hz, 3H); ESI MS m/z532 [C₂₆H₂₉NO₁₁+H]⁺; HPLC (Method A) 95.1% (AUC), t_(R)=7.64 min.

Preparation of (S)-4-tert-Butyl 1-(2,5-dioxopyrrolidin-1-yl)2-acetoxysuccinate

A solution of (S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoic acid (2.00 g,8.61 mmol) in tetrahydrofuran (60 mL) was treated withN-hydroxysuccinimide (1.09 g, 9.47 mmol) andN,N′-dicyclohexylcarbodiimide (1.95 g, 9.47 mmol) and stirred under anitrogen atmosphere for 4 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (3.37 g) as a brown oil:¹H NMR (300 MHz, CDCl₃) δ 5.76 (dd, J=8.1, 4.8 Hz, 1H), 3.01-2.88 (m,2H), 2.84 (s, 4H), 2.14 (s, 3H), 1.46 (s, 9H).

Preparation of(S)-1-((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-acetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-4-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (451mg, 1.37 mmol) in tetrahydrofuran (5 mL). After addition was complete,the mixture was warmed to 0° C. After this time, the reaction mixturewas treated with saturated aqueous ammonium chloride (20 mL) andextracted with ethyl acetate (2×50 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (40 g silica gelcolumn, 0-20% methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-acetoxysuccinate (278 mg, 36%) as a white solid: ESI MSm/z 616 [C₃₂H₄₁NO₁₁+H]⁺.

Preparation of(S)-3-Acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(S)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2-acetoxysuccinate (139 mg, 0.226 mmol) in methylenechloride (3 mL) was treated with trifluoroacetic acid (3 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 1 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 0-100% acetonitrile/water with 0.1% trifluoroacetic acid) andfreeze dried to provide(S)-3-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (38 mg, 28%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 12.8 (br s, 1H), 9.29 (s, 1H), 9.16 (br s, 1H),6.65 (apparent q, J=8.1 Hz, 2H), 6.26 (s, 1H), 5.60 (dd, J=5.7, 2.1 Hz,1H), 5.39 (dd, J=7.2, 4.2 Hz, 1H), 4.92 (s, 1H), 3.62-3.34 (m, 1H),3.11-2.83 (m, 7H), 2.73-2.39 (m, 3H), 2.29 (m, 1H), 2.11 (s, 3H), 2.06(m, 1H), 1.62 (m, 1H); ESI MS m/z 460 [C₂₃H₂₅NO₉+H]⁺.

Preparation of(S)-2-(((S)-2-Acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid

(S)-Mandelic acid (770 mg, 5.06 mmol), (S)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (2.00 g, 6.07 mmol),4-(dimethylamino)pyridine (62 mg, 0.506 mmol), pyridine (480 mg, 6.07mmol) and tetrahydrofuran (34 mL) were combined and heated at 60° C.under a nitrogen atmosphere for 24 h. After this time, the solvent wasremoved under reduced pressure, and the residue was participated betweenethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer wasseparated and extracted with saturated aqueous sodium bicarbonate (20ml). The aqueous phase was collected and acidified to pH=3 with 6 Nhydrochloric acid, and the mixture was extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(S)-2-(((S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid (754 mg, 41%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ7.48-7.39 (m, 5H), 6.03 (s, 1H), 5.54 (m, 1H), 3.01-2.76 (m, 2H), 2.13(s, 3H), 1.45 (s, 9H), CO₂H proton not observed.

Preparation of (S)-4-tert-Butyl1-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate

A solution of(S)-2-(((S)-2-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid (754 mg, 2.06 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (260 mg, 2.26 mmol) andN,N′-dicyclohexylcarbodiimide (466 mg, 2.26 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-4-tert-butyl1-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate (930 mg) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ7.55-7.43 (m, 5H), 6.39 (s, 1H), 5.53 (m, 1H), 2.98-2.76 (m, 6H), 2.15(s, 3H), 1.46 (s, 9H).

Preparation of(S)-1-((S)-2-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)4-tert-butyl 2-acetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (400 mg, 0.996 mmol) in tetrahydrofuran (8 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.2 mL, 1.2 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-4-tert-butyl1-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate (508 mg, 1.10 mmol) in tetrahydrofuran (5 mL). Afteraddition was complete, the mixture was warmed to 0° C. After this time,the reaction mixture was treated with saturated aqueous ammoniumchloride (20 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (40 g silica gel column, 0-20% methanol/methylenechloride, then 50 g C18 column, 10-100% acetonitrile/water) to provide(S)-1-((S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)4-tert-butyl 2-acetoxysuccinate (160 mg, 21%) as a white solid: ESI MSm/z 750 [C₄₀H₄₇NO₁₃+H]⁺.

Preparation of(S)-3-Acetoxy-4-((S)-2-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(S)-1-((S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)4-tert-butyl 2-acetoxysuccinate (160 mg, 0.213 mmol) in methylenechloride (3 mL) was treated with trifluoroacetic acid (3 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 2 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 0-100% acetonitrile/water with 0.1% trifluoroacetic acid) andfreeze dried to provide(S)-3-acetoxy-4-((S)-2-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid trifluoroacetic acid salt (86 mg, 57%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 12.8 (br s, 1H), 9.34 (s, 1H), 9.27 (br s, 1H),7.60-7.54 (m, 2H), 7.49-7.45 (m, 3H), 6.68 (d, J=8.1 Hz, 1H), 6.66 (d,J=8.1 Hz, 1H), 6.24 (s, 2H), 5.58 (dd, J=5.7, 2.1 Hz, 1H), 5.44 (dd,J=9.0, 3.6 Hz, 1H), 4.86 (s, 1H), 3.40-3.33 (m, 2H), 3.07-2.99 (m, 2H),2.89-2.82 (m, 4H), 2.63-2.39 (m, 4H), 2.25 (m, 1H), 2.09-2.02 (m, 3H),1.59 (m, 1H); ESI MS m/z 594 [C₃₁H₃₁NO₁₁+H]⁺; HPLC (Method A) 98.9%(AUC), t_(R)=8.92 min.

Preparation of(2R,3R)-2,3-Diacetoxy-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid and(2R,3R)-2,3-Diacetoxy-4-((R)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid

A solution of (3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate (1.35g, 6.25 mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. was treatedwith (S)-tert-butyl 2-hydroxy-2-phenylacetate (˜7:3 S/R mixture, 1.02 g,4.90 mmol) followed by pyridine (0.36 mL, 4.47 mmol), and the mixturewas stirred at 0° C. for 1 h. After this time, the reaction mixture wasdiluted with ethyl acetate; washed with 10% citric acid, water, andbrine; filtered; and concentrated. The residue was purified by reversedphase column chromatography (150 g C18 column, 3-20% acetonitrile/water)to provide(2R,3R)-2,3-diacetoxy-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (dr 95:5, 1.47 g, 54%) and(2R,3R)-2,3-diacetoxy-4-((R)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (dr 85:15, 0.55 g, 18%).(2R,3R)-2,3-Diacetoxy-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid: ¹H NMR (300 MHz, CDCl₃) δ 7.26 (s, 5H), 5.94 (s, 1H), 5.90 (d,J=2.6 Hz, 1H), 5.81 (s, J=2.6 Hz, 1H), 2.17 (s, 3H), 1.92 (s, 3H), 1.40(s, 9H), CO₂H proton not observed.

Preparation of (2R,3R)-1-((S)-2-(tert-Butoxy)-2-oxo-1-phenylethyl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate

A mixture of(2R,3R)-2,3-diacetoxy-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (1.07 g, 2.52 mmol) and N-hydroxysuccinimide (320 mg, 2.78 mmol) intetrahydrofuran (14 mL) was treated with N,N′-dicyclohexylcarbodiimide(570 mg, 2.76 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (20 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide(2R,3R)-1-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (1.41 g, 80%) thatwas used without purification: ¹H NMR (300 MHz, CDCl₃) δ 7.38 (s, 5H),6.14 (d, J=2.8 Hz, 1H), 6.02 (d, J=2.8 Hz, 1H), 5.92 (s, 1H), 2.83 (s,4H), 2.24 (s, 3H), 1.97 (s, 3H), 1.41 (s, 9H).

Preparation of (2R,3R)-1-((S)-2-(tert-Butoxy)-2-oxo-1-phenylethyl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (400 mg, 1.00 mmol) in tetrahydrofuran (8 mL) was cooled to 0°C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.1 mL, 1.1 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to 0° C., and(2R,3R)-1-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (550 mg, 1.06 mmol)was added in one portion. The mixture was stirred at 0° C. for 45 min.After this time, the mixture was treated with saturated aqueous ammoniumchloride and extracted with ethyl acetate. The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 10-100% acetonitrile/water) to provide(2R,3R)-1-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (270 mg, 33%): ESI MS m/z 808 [C₄₂H₄₉NO₁₅+H]⁺.

Preparation of(S)-2-(((2R,3R)-2,3-Diacetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt

A solution of (2R,3R)-1-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (270 mg, 0.33 mmol) in methylene chloride (6 mL)was treated with trifluoroacetic acid (1 mL) and stirred at ambienttemperature for 4 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 3-30%acetonitrile/water, with 0.1% trifluoracetic acid) and freeze dried toprovide(S)-2-(((2R,3R)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt (42 mg, 20%): ¹H NMR (300 MHz, DMSO-d₆) δ9.35 (s, 1H), 9.15 (br s, 1H), 7.46-7.40 (m, 5H), 6.68 (d, J=8.2 Hz,1H), 6.63 (d, J=8.2 Hz, 1H), 6.30 (s, 1H), 6.01 (s, 1H), 5.96 (d, J=2.7Hz, 1H), 5.86 (d, J=2.7 Hz, 1H), 5.56-5.51 (m, 1H), 4.83 (s, 1H), 3.62(d, J=6.2 Hz, 1H), 3.11-3.01 (m, 1H), 3.83 (s, 3H), 2.70-2.54 (m, 1H),2.49-2.39 (m, 1H), 2.32-2.16 (m, 5H), 2.07 (d, J=18.0 Hz, 1H), 2.01 (s,3H), 1.62 (d, J=12.0 Hz, 1H), CO₂H proton not observed; ESI MS m/z 652[C₃₃H₃₃NO₁₃+H]⁺; HPLC (Method A) 98.7% (AUC), t_(R)=9.12 min.

Preparation of(S)-2-(((S)-5-(tert-Butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoicacid

(S)-Lactic acid (270 mg, 3.00 mmol), (S)-1-tert-butyl5-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)amino)pentanedioate(1.00 g, 2.50 mmol), 4-(dimethylamino)pyridine (31 mg, 0.250 mmol), andpyridine (237 mg, 3.00 mmol) were combined and heated at 60° C. under anitrogen atmosphere for 48 h. After this time, the solvent was removedunder reduced pressure, and the residue was participated between ethylacetate (20 mL) and 10% aqueous citric acid. The organic layer wasseparated and extracted with saturated aqueous sodium bicarbonate (20ml). The aqueous phase was collected and acidified to pH=3 with 6 Nhydrochloric acid, and the mixture was extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(S)-2-(((S)-5-(tert-butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoicacid (726 mg, 77%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ5.19-5.12 (m, 2H), 2.51-2.42 (m, 2H), 2.18 (m, 1H), 1.91 (m, 1H), 1.54(d, J=7.2 Hz, 3H), 1.47 (s, 9H), 1.45 (s, 9H), CO₂H and NH protons notobserved.

Preparation of (S)-1-tert-Butyl5-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate

A solution of(S)-2-(((S)-5-(tert-butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoyl)oxy)propanoicacid (726 mg, 1.93 mmol) in tetrahydrofuran (15 mL) was treated withN-hydroxysuccinimide (245 mg, 2.13 mmol) andN,N′-dicyclohexylcarbodiimide (439 mg, 2.13 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-1-tert-butyl5-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (1.03 g, quantitative) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 5.42 (dd, J=14.1, 7.2 Hz, 1H),5.08 (m, 1H), 2.84 (s, 4H), 2.53-2.46 (m, 2H), 2.20 (m, 1H), 1.91 (m,1H), 1.67 (d, J=7.2 Hz, 3H), 1.47 (s, 9H), 1.45 (s, 9H), NH proton notobserved.

Preparation of(S)-5-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)1-tert-butyl 2-((tert-butoxycarbonyl)amino)pentanedioate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (400 mg, 0.996 mmol) in tetrahydrofuran (8 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.2 mL, 1.2 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-1-tert-butyl5-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)pentanedioate (518 mg, 1.10 mmol) intetrahydrofuran (5 mL). After addition was complete, the mixture waswarmed to 0° C. After this time, the reaction mixture was treated withsaturated aqueous ammonium chloride (20 mL) and extracted with ethylacetate (2×50 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)-5-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)1-tert-butyl 2-((tert-butoxycarbonyl)amino)pentanedioate (264 mg, 35%)as a white solid: ESI MS m/z 759 [C₃₉H₅₄N₂O₁₃+H]⁺.

Preparation of(S)-2-Amino-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid bis(trifluoroacetic acid salt)

A solution of(S)-5-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)1-tert-butyl 2-((tert-butoxycarbonyl)amino)pentanedioate (160 mg, 0.211mmol) in methylene chloride (3 mL) was treated with trifluoroacetic acid(3 mL) and stirred under a nitrogen atmosphere at ambient temperaturefor 3 h. After this time, the reaction mixture was concentrated underreduced pressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 0-100% acetonitrile/water with 0.1%trifluoroacetic acid) and freeze dried to provide(S)-2-amino-5-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-5-oxopentanoicacid bis(trifluoroacetic acid salt) (76 mg, 47%) as a fluffy whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (br s, 1H), 9.16 (br s, 1H),8.27 (br s, 3H), 6.66 (apparent q, J=8.1 Hz, 2H), 6.26 (s, 1H), 5.58(dd, J=6.0, 2.1 Hz, 1H), 5.13 (q, J=4.2 Hz, 1H), 4.96 (s, 1H), 3.96 (m,1H), 3.44 (m, 2H), 3.05 (m, 1H), 2.84 (s, 3H), 2.73-2.41 (m, 5H), 2.28(m, 1H), 2.18-2.00 (m, 3H), 1.62 (m, 1H), 1.53 (d, J=7.2 Hz, 3H), CO₂Hproton not observed; ESI MS m/z 503 [C₂₅H₃₀N₂O₉+H]⁺; HPLC (Method A)95.0% (AUC), t_(R)=6.38 min.

Preparation of(S)-3-Acetoxy-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid

A solution of (S)-2,5-dioxotetrahydrofuran-3-yl acetate (0.70 g, 3.4mmol) and (S)-tert-butyl 2-hydroxypropanoate (0.50 g, 3.4 mmol) inN,N-dimethylformamide (4 mL) was cooled in an ice bath and treated withpyridine (0.36 mL, 4.4 mmol). After addition was complete, the mixturewas stirred at ambient temperature for 16 h. After this time, themixture was diluted with water (20 mL) and extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(S)-3-acetoxy-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (0.6 g, 58%) as a brown oil: ¹H NMR (300 MHz, CDCl₃) ¹H NMR (300MHz, CDCl₃) δ 5.49 (dd, J=9.3, 3.3 Hz, 1H), 5.03 (dd, J=14.1, 6.9 Hz,1H), 3.13 (dd, J=17.1, 3.3 Hz, 1H), 2.95 (dd, J=17.1, 9.3 Hz, 1H), 2.13(s, 3H), 1.48 (d, J=7.2 Hz, 3H), 1.46 (s, 9H), CO₂H proton not observed.

Preparation of (S)-1-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate

(S)-3-Acetoxy-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (1.8 g, 6.01 mmol), 1-hydroxypyrrolidine-2,5-dione (0.81 g, 7.0mmol) and dicyclohexylcarbodiimide (1.36 g, 6.61 mmol) were combined andstirred in tetrahydrofuran (40 mL) at ambient temperature for 4 h. Afterthis time, the mixture was filtered and concentrated under reducedpressure to provide (S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (2.64 g, 99%) as asticky solid: ¹H NMR (300 MHz, DMSO-d₆) δ 5.50 (dd, J=8.7, 4.2 Hz, 1H),5.00 (dd, J=14.1, 6.9 Hz, 1H), 3.40 (dd, J=17.1, 3.3 Hz, 1H), 3.30 (dd,J=17.1, 9.3 Hz, 1H), 2.77 (s, 4H), 2.10 (s, 3H), 1.46 (d, J=6.9 Hz, 3H),1.41 (s, 9H).

Preparation of (S)-1-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2-acetoxysuccinate (550 mg, 1.37 mmol) intetrahydrofuran (5 mL). After addition was complete, the mixture waswarmed to 0° C. After this time, the reaction mixture was treated withsaturated aqueous ammonium chloride (20 mL) and extracted with ethylacetate (2×50 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate (293 mg, 34%) as a white solid: ESI MS m/z 688[C₃₅H₄₅NO₁₃+H]⁺.

Preparation of(S)-2-(((S)-2-Acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt

A solution of (S)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-acetoxysuccinate (150 mg, 0.218 mmol) in methylene chloride (3 mL) wastreated with trifluoroacetic acid (3 mL) and stirred under a nitrogenatmosphere at ambient temperature for 1 h. After this time, the reactionmixture was concentrated under reduced pressure. The residue waspurified by reversed phase column chromatography (50 g C18 column,0-100% acetonitrile/water with 0.1% trifluoroacetic acid) and freezedried to provide(S)-2-(((S)-2-acetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt (55 mg, 37%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 13.2 (br s, 1H), 9.29 (s, 1H), 9.15 (br s, 1H),6.65 (apparent q, J=8.1 Hz, 2H), 6.23 (s, 1H), 5.58 (dd, J=6.3, 2.1 Hz,1H), 5.42 (dd, J=9.3, 3.6 Hz, 1H), 5.09-4.97 (m, 2H), 3.43-3.33 (m, 1H),3.18 (dd, J=17.1, 3.6 Hz, 1H), 3.11-2.93 (m, 3H), 2.84 (s, 3H),2.73-2.42 (m, 3H), 2.28 (m, 1H), 2.13-2.04 (m, 4H), 1.63 (m, 1H), 1.43(d, J=7.2 Hz, 3H); ESI MS m/z 532 [C₂₆H₂₉NO₁₁+H]⁺.

Preparation of (2R,3R)-1-((R)-2-(tert-Butoxy)-2-oxo-1-phenylethyl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate

A mixture of(2R,3R)-2,3-diacetoxy-4-((R)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid (550 mg, 1.30 mmol) and N-hydroxysuccinimide (165 mg, 1.43 mmol) intetrahydrofuran (8 mL) was treated with N,N′-dicyclohexylcarbodiimide(295 mg, 1.43 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (10 mL) was addedand the mixture was filtered. The filtrate was concentrated underreduced pressure to provide(2R,3R)-1-((R)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (1.41 g, 80%) thatwas used without purification: ¹H NMR (300 MHz, CDCl₃) δ 7.41-7.38 (m,5H), 6.33 (d, J=2.8 Hz, 1H), 5.95 (d, J=2.8 Hz, 1H), 5.79 (s, 1H), 2.83(s, 4H), 2.29 (s, 3H), 2.28 (s, 3H), 1.35 (s, 9H).

Preparation of (2R,3R)-1-((R)-2-(tert-Butoxy)-2-oxo-1-phenylethyl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (300 mg, 0.75 mmol) in tetrahydrofuran (6 mL) was cooled to 0°C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (0.75 mL, 0.75 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to 0° C., and(2R,3R)-1-((R)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (355 mg, 0.681 mmol)was added in one portion. The mixture was stirred at 0° C. for 45 min.After this time, the mixture was treated with saturated aqueous ammoniumchloride and extracted with ethyl acetate. The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 10-100% acetonitrile/water) to provide(2R,3R)-1-((R)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (260 mg, 47%): ESI MS m/z 808 [C₄₂H₄₉NO₁₅+H]⁺.

Preparation of(R)-2-(((2R,3R)-2,3-Diacetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic

A solution of (2R,3R)-1-((R)-2-(tert-butoxy)-2-oxo-1-phenylethyl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (260 mg, 0.32 mmol) in methylene chloride (6 mL)was treated with trifluoroacetic acid (1 mL) and stirred at ambienttemperature for 3 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 3-30%acetonitrile/water, with 0.1% trifluoracetic acid) and freeze dried toprovide(R)-2-(((2R,3R)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt (74 mg, 36%): ¹H NMR (300 MHz, DMSO-d₆) δ13.51 (br s, 1H), 9.33 (s, 1H), 9.15 (br s, 1H), 7.51-7.40 (m, 5H), 6.67(d, J=8.2 Hz, 1H), 6.62 (d, J=8.2 Hz, 1H), 6.30 (s, 1H), 6.03 (d, J=2.7Hz, 1H), 5.98-5.94 (m, 2H), 5.56-5.53 (m, 1H), 4.83 (s, 1H), 3.62 (d,J=6.0 Hz, 1H), 3.40-3.33 (m, 1H), 3.12-3.02 (m, 2H), 3.83 (apparent d,J=3.5 Hz, 3H), 2.67-2.56 (m, 1H), 2.47-2.38 (m, 1H), 2.31-2.21 (m, 4H),2.11 (s, 3H), 2.08 (d, J=17.7 Hz, 1H), 1.63 (d, J=11.1 Hz, 1H); ESI MSm/z 652 [C₃₃H₃₃NO₁₃+H]⁺; HPLC (Method A) 98.0% (AUC), t_(R)=9.16 min.

Preparation of (2R,3R)-2,3-Diacetoxy-4-methoxy-4-oxobutanoic acid

A mixture of (3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate (5.66g, 26.2 mmol) in methanol (26 mL) was stirred at room temperature for 30min. After this time, the mixture was concentrated to dryness to provide(2R,3R)-2,3-diacetoxy-4-methoxy-4-oxobutanoic acid (6.30 g, 97%): ¹H NMR(300 MHz, DMSO-d₆) δ 5.63 (d, J=2.9 Hz, 1H), 5.52 (d, J=2.9 Hz, 1H),3.70 (s, 3H), 2.12 (s, 3H), 2.10 (s, 3H), CO₂H proton not observed.

Preparation of (2R,3R)-1-tert-Butyl 4-methyl 2,3-diacetoxysuccinate

A mixture of (2R,3R)-2,3-diacetoxy-4-methoxy-4-oxobutanoic acid (6.30 g,25.4 mmol) and tert-butanol (6.5 mL, 68 mmol) in methylene chloride (50mL) at 0° C. was treated with N,N′-dicyclohexylcarbodiimide (6.70 g,32.5 mmol). After stirring for 1 h, the ice bath was removed and thereaction mixture was stirred at ambient temperature for 18 h. After thistime, the mixture was filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by column chromatography (120g silica gel column, 5-70% ethyl acetate/heptane) to provide(2R,3R)-1-tert-butyl 4-methyl 2,3-diacetoxysuccinate (4.2 g, 54%): ¹HNMR (300 MHz, CDCl₃) δ 5.73 (d, J=2.8 Hz, 1H), 5.60 (d, J=2.8 Hz, 1H),3.78 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H), 1.45 (s, 9H).

Preparation of (2R,3R)-1-tert-Butyl 4-methyl 2,3-dihydroxysuccinate

A solution of (2R,3R)-1-tert-butyl 4-methyl 2,3-diacetoxysuccinate (4.15g, 13.7 mmol) in methanol (28 mL) was treated with sodium methoxide (25%in methanol, 0.30 mL, 1.3 mmol), and the mixture was stirred at roomtemperature for 19 h. After this time, the reaction mixture was treatedwith a few drops of 2 N hydrochloric acid, until neutral by pH paperanalysis. The mixture was partially concentrated, and the residue wasdissolved in ethyl acetate, washed with saturated ammonium chloride andbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure to provide (2R,3R)-1-tert-butyl 4-methyl2,3-dihydroxysuccinate (2.62 g, 87%): ¹H NMR (300 MHz, CDCl₃) δ 4.51(dd, J=7.5, 1.7 Hz, 1H), 4.41 (d, J=6.3, 1.7 Hz, 1H), 3.86 (s, 3H), 3.19(d, J=6.3 Hz, 1H), 3.05 (d, J=7.5 Hz, 1H), 1.52 (s, 9H).

Preparation of (4R,5R)-4-tert-Butyl 5-methyl2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A mixture of (2R,3R)-1-tert-butyl 4-methyl 2,3-dihydroxysuccinate (2.62g, 11.9 mmol), 2,2-dimethoxypropane (2.2 mL, 18 mmol), andp-toluensulfonic acid (50 mg, 0.26 mmol) in benzene (30 mL) was stirredat reflux for 20 h. After this time, the mixture was cooled to roomtemperature, and saturated sodium bicarbonate was added. The mixture wasstirred for 5 min and then extracted with ethyl acetate. The organicextracts were washed with water and brine and then concentrated. Theresidue was purified by column chromatography (80 g silica gel column,5-70% ethyl acetate/heptane) to provide (4R,5R)-4-tert-butyl 5-methyl2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (1.63 g, 53%): ¹H NMR (300MHz, CDCl₃) δ 4.71 (d, J=5.9 Hz, 1H), 4.64 (d, J=5.9 Hz, 1H), 3.82 (s,3H), 1.50 (s, 15H).

Preparation of(4R,5R)-5-(tert-Butoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid

A solution of (4R,5R)-4-tert-butyl 5-methyl2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (4.96 g, 19.1 mmol) intetrahydrofuran (35 mL) was treated with a solution of lithium hydroxide(940 mg, 22.4 mmol) in water (15 mL), and the mixture was stirred atroom temperature for 1 h. After this time, 2 N hydrochloric acid wasadded until the mixture tested neutral by pH paper analysis. The mixturewas partially concentrated and then extracted with ethyl acetate. Theorganic extracts were washed with 10% citric acid and brine, dried oversodium sulfate, filtered and concentrated to provide(4R,5R)-5-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid (2.00 g, 43%): ¹H NMR (300 MHz, CDCl₃) δ 4.80 (d, J=5.7 Hz, 1H),4.66 (d, J=5.7 Hz, 1H), 1.53 (s, 3H), 1.52 (s, 9H), 1.50 (s, 3H), CO₂Hproton not observed.

Preparation of (4R,5R)-4-tert-Butyl 5-(2,5-dioxopyrrolidin-1-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A mixture of(4R,5R)-5-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid (410 mg, 1.67 mmol) and N-hydroxysuccinimide (210 mg, 1.82 mmol) intetrahydrofuran (10 mL) was treated with N,N′-dicyclohexylcarbodiimide(380 mg, 1.84 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (20 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide (4R,5R)-4-tert-butyl5-(2,5-dioxopyrrolidin-1-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (650 mg) that was usedwithout purification: ¹H NMR (300 MHz, CDCl₃) δ 5.09 (d, J=4.9 Hz, 1H),4.87 (d, J=4.9 Hz, 1H), 2.87 (s, 4H), 1.54 (s, 3H), 1.52 (s, 3H), 1.51(s, 9H).

Preparation of(4R,5R)-4-((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)5-tert-butyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (400 mg, 1.00 mmol) in tetrahydrofuran (8 mL) was cooled to 0°C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.1 mL, 1.1 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to 0° C. and (4R,5R)-4-tert-butyl5-(2,5-dioxopyrrolidin-1-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (500 mg, 1.09 mmol) wasadded in one portion. The mixture was stirred at 0° C. for 1 h. Afterthis time, the mixture was treated with saturated aqueous ammoniumchloride and extracted with ethyl acetate. The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 5-100% acetonitrile/water) to provide(4R,5R)-4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)5-tert-butyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (254 mg, 40%):ESI MS m/z 630 [C₃₃H₄₃NO₁₁+H]⁺.

Preparation of(2R,3R)-1-((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2,3-dihydroxysuccinate

A solution of(4R,5R)-4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)5-tert-butyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (245 mg, 0.390mmol) in 1,4-dioxane (2 mL) and water (0.1 mL) was treated with a 1 Nsolution of hydrogen chloride in 1,4-dioxane (2 mL, 8 mmol) and stirredat ambient temperature for 3 h. After this time, the reaction mixturewas concentrated under reduced pressure to provide(2R,3R)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2,3-dihydroxysuccinate (240 mg): ESI MS m/z 590[C₃₀H₃₉NO₁₁+H]⁺.

Preparation of(2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(2R,3R)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-tert-butyl 2,3-dihydroxysuccinate (240 mg) in methylene chloride (5mL) was treated with trifluoroacetic acid (1.5 mL) and stirred atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 3-10%acetonitrile/water, with 0.1% trifluoracetic acid) and freeze dried toprovide(2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoicacid trifluoroacetic acid salt (7 mg, 3% over two steps): ¹H NMR (300MHz, CD₃OD) δ 6.65-6.57 (m, 2H), 5.55 (dd, J=5.4, 2.8 Hz, 1H), 4.99 (s,1H), 4.65 (d, J=2.2 Hz, 1H), 4.53 (d, J=2.2 Hz, 1H), 3.56 (d, J=6.5 Hz,1H), 3.35 (d, J=20.0 Hz, 1H), 3.13-3.03 (m, 2H), 2.83 (s, 3H), 2.82-2.74(m, 1H), 2.57 (dt, J=13.4, 4.9 Hz, 1H), 2.25-2.17 (m, 2H), 1.71 (dd,J=13.5, 3.0 Hz, 1H), CO₂H, CF₃CO₂H, and four OH protons not observed;ESI MS m/z 434 [C₂₁H₂₃NO₉+H]⁺; HPLC (Method A) 93.3% (AUC), t_(R)=5.83min.

Preparation of(2S,3S)-2,3-Diacetoxy-4-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (370 mg, 0.92 mmol) in tetrahydrofuran (8 mL) at 0° C. wastreated with a 1.0 M solution of lithium bis(trimethylsilyl)amide intetrahydrofuran (0.95 mL, 0.95 mmol), and the mixture was stirred for 5min at 0° C. and 10 min at room temperature. The reaction mixture wascooled to 0° C. and (3S,4S)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate(89 mg, 0.41 mmol) was added in one portion. The mixture was stirred at0° C. for 20 min and then at room temperature for 30 min. After thistime, the mixture was poured into a saturated solution of ammoniumchloride and extracted with ethyl acetate. The organic extract was driedover sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by reversed phase column chromatography (50 gC18 column, 5-80% acetonitrile/water) and freeze dried to provide(2S,3S)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid (50 mg, 9%): ESI MS m/z 618 [C₃₀H₃₅NO₁₃+H]⁺.

Preparation of(2S,3S)-2,3-Diacetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(2S,3S)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid (45 mg, 0.073 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (0.8 mL) and stirred at ambient temperature for 45min. After this time, the reaction mixture was concentrated underreduced pressure. The residue was purified by reversed phase columnchromatography (15.5 g C18 column, 3-30% acetonitrile/water, with 0.1%trifluoracetic acid) and freeze dried to provide(2S,3S)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (30 mg, 62%): ¹H NMR (300 MHz, DMSO-d₆) δ9.24 (br s, 1H), 9.16 (br s, 1H), 6.87 (d, J=8.2 Hz, 1H), 6.62 (d, J=8.2Hz, 1H), 6.30 (s, 1H), 5.82 (d, J=2.9 Hz, 1H), 5.60 (dd, J=6.0, 1.9 Hz,1H), 5.56 (d, J=2.9 Hz, 1H), 4.94 (s, 1H), 3.63 (d, J=6.0 Hz, 1H),3.42-3.30 (m, 1H), 3.11-3.02 (m, 2H), 2.84 (apparent d, J=3.8 Hz, 3H),2.70-2.56 (m, 1H), 2.48-2.39 (m, 1H), 2.28 (d, J=18.0, 6.1 Hz, 1H), 2.18(s, 3H), 2.15 (s, 3H), 2.11-2.02 (m, 1H), 1.63 (d, J=11.3 Hz, 1H), CO₂Hproton not observed; ESI MS m/z 518 [C₂₅H₂₇NO₁₁+H]⁺; HPLC (Method A)96.8% (AUC), t_(R)=7.19 min.

Preparation of(2R,3R)-2,3-Diacetoxy-4-(((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid

(S)-Di-tert-butyl 2-hydroxysuccinate (968 mg, 3.93 mmol),(3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate (1.06 g, 4.91 mmol),pyridine (279 mg, 3.54 mmol), and N,N-dimethylformamide (2 mL) werecombined and stirred at 0° C. under a nitrogen atmosphere for 2 h. Afterthis time, saturated sodium bicarbonate (15 mL) was added, and theresulting aqueous solution was washed with ethyl acetate (10 mL). Theaqueous phase was collected and acidified to pH=3 with 6 N hydrochloricacid, and the mixture was extracted with ethyl acetate (2×20 mL). Thecombined organics were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(2R,3R)-2,3-diacetoxy-4-(((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid (1.74 g, 95%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.80 (d,J=3.0 Hz, 1H), 5.68 (d, J=3.0 Hz, 1H), 5.30 (dd, J=7.2, 5.1 Hz, 1H),2.77-2.74 (m, 2H), 2.20 (s, 3H), 2.18 (s, 3H), 1.46 (s, 9H), 1.44 (s,9H), CO₂H proton not observed.

Preparation of (2R,3R)-1-((S)-1,4-Di-tert-butoxy-1,4-dioxobutan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate

A solution of(2R,3R)-2,3-diacetoxy-4-(((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid (1.74 g, 3.76 mmol) in tetrahydrofuran (25 mL) was treated withN-hydroxysuccinimide (476 mg, 4.14 mmol) andN,N′-dicyclohexylcarbodiimide (929 mg, 4.51 mmol) and stirred under anitrogen atmosphere for 4 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide(2R,3R)-1-((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (2.06 g) as a yellowsolid: ¹H NMR (300 MHz, CDCl₃) δ 6.04 (d, J=3.0 Hz, 1H), 5.95 (d, J=2.7Hz, 1H), 5.32 (dd, J=8.1, 4.2 Hz, 1H), 2.85-2.74 (m, 6H), 2.25 (s, 3H),2.23 (s, 3H), 1.46 (s, 9H), 1.44 (s, 9H).

Preparation(2R,3R)-1-((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl) 2,3-diacetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled to −45° C. and treated dropwisewith a solution of(2R,3R)-1-((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (766 mg, 1.37 mmol)in tetrahydrofuran (5 mL). After addition was complete, the mixture waswarmed to 0° C. After this time, the reaction mixture was treated withsaturated aqueous ammonium chloride (20 mL) and extracted with ethylacetate (2×25 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(2R,3R)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl) 2,3-diacetoxysuccinate(290 mg, 27%) as a white solid: ESI MS m/z 846 [C₄₂H₅₅NO₁₇+H]⁺.

Preparation of(S)-2-(((2R,3R)-2,3-Diacetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid trifluoroacetic acid salt

A solution of(2R,3R)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl) 2,3-diacetoxysuccinate(290 mg, 0.343 mmol) in methylene chloride (5.0 mL) was treated withtrifluoroacetic acid (5.0 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-2-(((2R,3R)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid trifluoroacetic acid salt (189 mg, 73%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 9.35 (s, 1H), 9.15 (br s, 1H), 6.64 (apparentq, J=8.1 Hz, 2H), 6.27 (br s, 1H), 5.85 (d, J=2.7 Hz, 1H), 5.77 (d,J=2.7 Hz, 1H), 5.53 (dd, J=5.7, 1.8 Hz, 1H), 5.29 (dd, J=8.4, 3.9 Hz,1H), 4.83 (s, 1H), 3.32 (m, 1H), 3.03 (m, 1H), 2.90-2.63 (m, 6H),2.51-2.41 (m, 3H), 2.27 (m, 1H), 2.21 (s, 3H), 2.13 (s, 3H), 2.04 (m,1H), 1.62 (m, 1H), CO₂H protons not observed; ESI MS m/z 634[C₂₉H₃₁NO₁₅+H]⁺.

Preparation of(S)-2-((4-(tert-Butoxy)-4-oxobutanoyl)oxy)-4-ethoxy-4-oxobutanoic acid

A mixture of (S)-4-ethoxy-2-hydroxy-4-oxobutanoic acid (1.51 g, 9.32mmol), tert-butyl (2,5-dioxopyrrolidin-1-yl) succinate (2.65 g, 9.78mmol), pyridine (1.0 mL, 12 mmol), and 4-dimethylaminopyridine (150 mg,1.23 mmol) in tetrahydrofuran (40 mL) was stirred at reflux for 24 h.After this time, the mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate, washed with 10% citric acid, and extracted with saturatedsodium bicarbonate. The aqueous layer was collected, carefully treatedwith 6 N hydrochloric acid until acidic by pH paper analysis, and thenextracted with ethyl acetate. The organic extracts were dried oversodium sulfate, filtered, and concentrated to provide(S)-2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)-4-ethoxy-4-oxobutanoic acid(1.47 g, 49%): ¹H NMR (300 MHz, CDCl₃) δ 5.56 (t, J=6.0 Hz, 1H), 4.19(q, J=7.1 Hz, 2H), 2.93 (d, J=6.0 Hz, 2H), 2.71-2.52 (m, 4H), 1.44 (s,9H), 1.27 (t, J=7.1 Hz, 3H), CO₂H proton not observed.

Preparation of (S)-1-(2,5-Dioxopyrrolidin-1-yl) 4-ethyl2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate

A mixture of(S)-2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)-4-ethoxy-4-oxobutanoic acid(1.40 g, 4.40 mmol) and N-hydroxysuccinimide (560 mg, 4.87 mmol) intetrahydrofuran (25 mL) was treated with N,N′-dicyclohexylcarbodiimide(1.00 g, 4.85 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (20 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide (S)-1-(2,5-dioxopyrrolidin-1-yl) 4-ethyl2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate (1.9 g) that was usedwithout purification: ¹H NMR (300 MHz, CDCl₃) δ 5.82 (dd, J=7.1, 5.2 Hz,1H), 4.22 (dd, J=7.1 Hz, 2H), 3.05-3.03 (m, 2H), 2.84 (s, 4H), 2.72-2.65(m, 2H), 2.60-2.53 (m, 2H), 1.44 (s, 9H), 2.28 (t, J=7.1 Hz, 3H).

Preparation of(S)-1-((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-ethyl 2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled to0° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.35 mL, 1.35 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to 0° C. and(S)-1-(2,5-dioxopyrrolidin-1-yl) 4-ethyl2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate (570 mg, 1.37 mmol) wasadded in one portion. The mixture was stirred at 0° C. for 1 h. Afterthis time, the mixture was treated with saturated aqueous ammoniumchloride and extracted with ethyl acetate. The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 5-100% acetonitrile/water) to provide(S)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-ethyl 2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate (384 mg, 44%):ESI MS m/z 702 [C₃₆H₄₇NO₁₃+H]⁺.

Preparation of4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-ethoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(S)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-ethyl 2-((4-(tert-butoxy)-4-oxobutanoyl)oxy)succinate (380 mg, 0.54mmol) in methylene chloride (6 mL) was treated with trifluoroacetic acid(1.2 mL) and stirred at ambient temperature for 1.5 h. After this time,the reaction mixture was concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 3-20% acetonitrile/water, with 0.1% trifluoracetic acid) andfreeze dried to provide4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-ethoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (128 mg, 34%): ¹H NMR (300 MHz, DMSO-d₆)δ 12.30 (br s, 1H), 9.30 (br s, 1H), 9.17 (br s, 1H), 6.68 (d, J=8.2 Hz,1H), 6.63 (d, J=8.2 Hz, 1H), 6.27 (s, 1H), 5.60 (dd, J=6.0, 1.9 Hz, 1H),5.45 (t, J=5.9 Hz, 1H), 4.93 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.62 (d,J=6.0 Hz, 1H), 3.14-2.98 (m, 4H), 2.84 (apparent d, J=4.7 Hz, 3H),2.70-2.57 (m, 3H), 2.43 (dd, J=13.3, 4.5 Hz, 1H), 2.28 (dd, J=17.9, 6.0Hz, 1H), 2.05 (d, J=17.9 Hz, 1H), 1.63 (d, J=11.1 Hz, 1H), 1.21 (t,J=7.1 Hz, 3H), three protons obscured by solvent peaks; ESI MS m/z 546[C₂₇H₃₁NO₁₁+H]⁺; HPLC (Method A) 97.4% (AUC), t_(R)=7.94 min.

Preparation of(2R,3R)-2,3-Diacetoxy-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid

A solution of (3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate (1.25g, 5.78 mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. was treatedwith (S)-tert-butyl 2-hydroxypropanoate (675 mg, 4.62 mmol) followed bypyridine (0.36 mL, 4.47 mmol), and the mixture was stirred at 0° C. for1 h. After this time, the reaction mixture was diluted with ethylacetate and extracted with saturated sodium bicarbonate. The aqueousextracts were acidified with 6 N hydrochloric acid and then extractedwith ethyl acetate. The organic extracts were dried over sodium sulfate,filtered, and concentrated to provide(2R,3R)-2,3-diacetoxy-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (1.66 g, quantitative): ¹H NMR (300 MHz, CDCl₃) δ 5.85 (d, J=2.6Hz, 1H), 5.83 (d, J=2.6 Hz, 1H), 5.02 (q, J=7.0 Hz, 1H), 2.19 (s, 3H),2.19 (s, 3H), 1.47-1.43 (m, 12H), CO₂H proton not observed.

Preparation of (2R,3R)-1-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate

A mixture of(2R,3R)-2,3-diacetoxy-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (1.20 g, 3.31 mmol) and N-hydroxysuccinimide (410 mg, 3.56 mmol) intetrahydrofuran (20 mL) was treated with N,N′-dicyclohexylcarbodiimide(740 mg, 3.58 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (20 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide(2R,3R)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (1.60 g) that wasused without purification: ¹H NMR (300 MHz, CDCl₃) δ 6.20 (d, J=2.7 Hz,1H), 5.95 (d, J=2.7 Hz, 1H), 5.01 (q, J=7.0 Hz, 1H), 2.84 (s, 4H), 2.26(s, 3H), 2.22 (s, 3H), 1.47-1.43 (m, 12H).

Preparation of (2R,3R)-1-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled to0° C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.1 mL, 1.1 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to 0° C., and(2R,3R)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (550 mg, 1.06 mmol)was added in one portion. The mixture was stirred at 0° C. for 45 min.After this time, the mixture was treated with saturated aqueous ammoniumchloride, and extracted with ethyl acetate. The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 5-100% acetonitrile/water) to provide(2R,3R)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (324 mg, 35%): ESI MS m/z 746 [C₃₇H₄₇NO₁₅+H]⁺.

Preparation of(S)-2-(((2R,3R)-2,3-Diacetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt

A solution of (2R,3R)-1-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)4-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,3-diacetoxysuccinate (320 mg, 0.43 mmol) in methylene chloride (6 mL)was treated with trifluoroacetic acid (1.5 mL) and stirred at ambienttemperature for 4 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 3-20%acetonitrile/water, with 0.1% trifluoracetic acid) and freeze dried toprovide(S)-2-(((2R,3R)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt (154 mg, 49%): ¹H NMR (300 MHz, DMSO-d₆)δ 9.37 (br s, 1H), 9.17 (br s, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.63 (d,J=8.2 Hz, 1H), 6.33 (br s, 1H), 5.89 (d, J=2.7 Hz, 1H), 5.85 (d, J=2.7Hz, 1H), 5.55-5.53 (m, 1H), 5.05 (q, J=7.0 Hz, 1H), 4.84 (s, 1H), 3.63(d, J=6.2 Hz, 1H), 3.11-3.03 (m, 2H), 3.83 (apparent d, J=1.8 Hz, 3H),2.71-2.57 (m, 1H), 2.47-2.39 (m, 1H), 2.43 (dd, J=18.0, 6.3 Hz, 1H),2.22 (s, 3H), 2.15 (s, 3H), 2.07 (d, J=18.0 Hz, 1H), 1.62 (d, J=11.2 Hz,1H), 1.39 (d, J=7.0 Hz, 3H), CO₂H proton not observed; ESI MS m/z 590[C₂₈H₃₁NO₁₃+H]⁺; HPLC (Method A) 98.5% (AUC), t_(R)=8.04 min.

Preparation of(2R,3R)-2,3-Diacetoxy-4-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid

A solution of (3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate (1.85g, 8.56 mmol) in N,N-dimethylformamide (2.2 mL) at 0° C. was treatedwith (S)-benzyl 2-hydroxypropanoate (1.30 g, 7.21 mmol) followed bypyridine (0.53 mL, 6.58 mmol), and the mixture was stirred at 0° C. for1 h. After this time, the reaction mixture was diluted with ethylacetate and extracted with saturated sodium bicarbonate. The aqueouslayer was collected, carefully treated with 6 N hydrochloric acid untilacidic by pH paper analysis, and then extracted with ethyl acetate. Theorganic extracts were dried over sodium sulfate, filtered andconcentrated to give(2R,3R)-2,3-diacetoxy-4-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (2.80 g, 98%): ¹H NMR (300 MHz, CDCl₃) δ 7.38-7.33 (m, 5H),5.84-5.83 (m, 2H), 5.23-5.13 (m, 3H), 2.18 (s, 3H), 2.17 (s, 3H), 1.49(d, J=7.1 Hz, 3H), CO₂H proton not observed.

Preparation of (2R,3R)-1-((S)-1-(Benzyloxy)-1-oxopropan-2-yl)4-tert-butyl 2,3-diacetoxysuccinate

A mixture of(2R,3R)-2,3-diacetoxy-4-(((S)-1-(benzyloxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid (2.80 g, 7.07 mmol), tert-butanol (1.8 mL, 19 mmol), and4-dimethylaminopyridine (280 mg, 2.29 mmol) in methylene chloride (16mL) at 0° C. was treated with N,N′-dicyclohexylcarbodiimide (1.70 g,8.24 mmol). The ice bath was removed, and the reaction mixture wasstirred at ambient temperature for 4 h. After this time, the mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography (80 g silica gel column,0-70% ethyl acetate/heptane) to provide(2R,3R)-1-((S)-1-(benzyloxy)-1-oxopropan-2-yl) 4-tert-butyl2,3-diacetoxysuccinate (1.38 g, 43%): ¹H NMR (300 MHz, CDCl₃) δ7.38-7.31 (m, 5H), 5.85 (d, J=2.7 Hz, 1H), 5.69 (d, J=2.7 Hz, 1H),5.23-5.13 (m, 3H), 2.17 (s, 3H), 2.16 (s, 3H), 1.49 (d, J=7.1 Hz, 3H),1.45 (s, 9H).

Preparation of(S)-2-(((2R,3R)-2,3-Diacetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoicacid

A mixture of (2R,3R)-1-((S)-1-(benzyloxy)-1-oxopropan-2-yl) 4-tert-butyl2,3-diacetoxysuccinate (1.35 g, 2.99 mmol) and palladium (5% on carbon,180 mg) in ethanol (15 mL) was stirred at room temperature under balloonpressure hydrogen for 2 h. After this time, the reaction mixture waspurged with nitrogen and filtered through diatomaceous earth. Thefiltrate was concentrated under reduced pressure to provide(S)-2-(((2R,3R)-2,3-diacetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoicacid (1.01 g, 93%): ¹H NMR (300 MHz, CDCl₃) δ 5.80 (d, J=2.7 Hz, 1H),5.69 (d, J=2.7 Hz, 1H), 5.16 (q, J=7.1 Hz, 1H), 2.18 (s, 3H), 2.17 (s,3H), 1.53 (d, J=7.1 Hz, 3H), 1.46 (s, 9H), CO₂H proton not observed.

Preparation of (2R,3R)-1-tert-Butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2,3-diacetoxysuccinate

A mixture of(S)-2-(((2R,3R)-2,3-diacetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)propanoicacid (1.00 g, 2.76 mmol) and N-hydroxysuccinimide (350 mg, 3.04 mmol) intetrahydrofuran (20 mL) was treated with N,N′-dicyclohexylcarbodiimide(627 mg, 3.04 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (20 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide (2R,3R)-1-tert-butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2,3-diacetoxysuccinate (960 mg, 76%) that was used without purification:¹H NMR (300 MHz, CDCl₃) δ 5.82 (d, J=2.7 Hz, 1H), 5.66 (d, J=2.7 Hz,1H), 5.49 (q, J=7.1 Hz, 1H), 2.85 (s, 4H), 2.18 (s, 3H), 2.16 (s, 3H),1.67 (d, J=7.1 Hz, 3H), 1.46 (s, 9H).

Preparation of(2R,3R)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)4-tert-butyl 2,3-diacetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (400 mg, 1.00 mmol) in tetrahydrofuran (8 mL) was cooled to 0°C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.1 mL, 1.1 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to 0° C., and (2R,3R)-1-tert-butyl4-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2,3-diacetoxysuccinate (500 mg, 1.09 mmol) was added in one portion. Themixture was stirred at 0° C. for 45 min. After this time, the mixturewas treated with saturated aqueous ammonium chloride, and extracted withethyl acetate. The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by reversed phase column chromatography (50 g C18 column,5-100% acetonitrile/water) to provide(2R,3R)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)4-tert-butyl 2,3-diacetoxysuccinate (280 mg, 38%): ESI MS m/z 746[C₃₇H₄₇NO₁₅+H]⁺.

Preparation of(2R,3R)-2,3-Diacetoxy-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(2R,3R)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)4-tert-butyl 2,3-diacetoxysuccinate (280 mg, 0.38 mmol) in methylenechloride (5 mL) was treated with trifluoroacetic acid (1 mL) and stirredat ambient temperature for 5 h. After this time, the reaction mixturewas concentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 3-20%acetonitrile/water, with 0.1% trifluoracetic acid) and freeze dried toprovide(2R,3R)-2,3-diacetoxy-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (86 mg, 30%): ¹H NMR (300 MHz, DMSO-d₆) δ13.9 (br s, 1H), 9.29 (br s, 1H), 9.17 (br s 1H), 6.68 (d, J=8.2 Hz,1H), 6.63 (d, J=8.2 Hz, 1H), 6.26 (s, 1H), 5.72 (d, J=2.8 Hz, 1H), 5.62(d, J=2.8 Hz, 1H), 5.59 (dd, J=6.0, 2.2 Hz, 1H), 5.28 (q, J=7.0 Hz, 1H),5.00 (s, 1H), 3.62 (d, J=6.3 Hz, 1H), 3.37 (d, J=20.0 Hz, 1H), 3.13-3.01(m, 2H), 2.83 (apparent d, J=4.6 Hz, 3H), 2.70-2.57 (m, 1H), 2.43 (dd,J=14.5, 4.7 Hz, 1H), 2.29 (dd, J=17.9, 6.4 Hz, 1H), 2.14 (s, 3H),2.11-2.02 (m, 4H), 1.63 (d, J=10.8 Hz, 1H), 1.50 (d, J=7.0 Hz, 3H); ESIMS m/z 590 [C₂₈H₃₁NO₁₃+H]⁺; HPLC (Method A) 96.8% (AUC), t_(R)=7.82 min.

Preparation of(S)-2-(((S)-4-(tert-Butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoyl)oxy)propanoicacid

(S)-Lactic acid (280 mg, 3.11 mmol), (S)-4-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)amino)succinate(1.00 g, 2.59 mmol), 4-(dimethylamino)pyridine (32 mg, 0.259 mmol),pyridine (248 mg, 3.11 mmol), and tetrahydrofuran (17 mL) were combinedand heated at 60° C. under a nitrogen atmosphere for 24 h. After thistime, the solvent was removed under reduced pressure, and the residuewas participated between ethyl acetate (30 mL) and 10% aqueous citricacid. The organic layer was separated and washed with water (50 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure to provide(S)-2-(((S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoyl)oxy)propanoicacid (858 mg, 91%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.51(m, 1H), 4.58 (m, 1H), 2.96-2.69 (m, 2H), 1.55 (m, 3H), 1.45 (s, 18H),CO₂H and NH protons not observed.

Preparation of (S)-4-tert-Butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate

A solution of(S)-2-(((S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoyl)oxy)propanoicacid (858 mg, 2.37 mmol) in tetrahydrofuran (30 mL) was treated withN-hydroxysuccinimide (300 mg, 2.61 mmol) andN,N′-dicyclohexylcarbodiimide (538 mg, 2.61 mmol) and stirred at roomtemperature under a nitrogen atmosphere for 5 h. After this time, thereaction mixture was filtered to remove the solid dicyclohexylureabyproduct. The solid was washed with diethyl ether (50 mL), and thecombined filtrate and washings were concentrated under reduced pressure.The residue was triturated with diethyl ether to provide(S)-4-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate (1.24 g, quantitative) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 5.52 (m, 1H), 4.63 (m, 1H),2.97-2.73 (m, 6H), 1.68 (m, 3H), 1.45 (s, 18H); NH proton not observed.

Preparation of(S)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)4-tert-butyl 2-((tert-butoxycarbonyl)amino)succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-4-tert-butyl1-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)amino)succinate (628 mg, 1.37 mmol) intetrahydrofuran (2.5 mL). After addition was complete, the mixture waswarmed to 0° C. After this time, the reaction mixture was treated withsaturated aqueous ammonium chloride (10 mL) and extracted with ethylacetate (2×25 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)4-tert-butyl 2-((tert-butoxycarbonyl)amino)succinate (304 mg, 32%) as awhite solid: ESI MS m/z 745 [C₃₈H₅₂N₂O₁₃+H]⁺.

Preparation of(S)-3-Amino-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(S)-1-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)4-tert-butyl 2-((tert-butoxycarbonyl)amino)succinate (300 mg, 0.403mmol) in methylene chloride (5.0 mL) was treated with trifluoroaceticacid (3.0 mL) and stirred under a nitrogen atmosphere at ambienttemperature for 3 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-3-amino-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-4-oxobutanoicacid trifluoroacetic acid salt (170 mg, 58%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 9.15 (br s, 2H), 8.44 (br s, 2H), 6.66(apparent q, J=8.1 Hz, 2H), 6.26 (s, 2H), 5.59 (m, 1H), 5.33 (q, J=7.2Hz, 1H), 4.98 (s, 1H), 4.45 (m, 1H), 3.35 (m, 2H), 3.11-2.88 (m, 4H),2.84 (s, 3H), 2.73-2.42 (m, 3H), 2.29 (m, 1H), 2.06 (m, 1H), 1.64-1.53(m, 4H); ESI MS m/z 489 [C₂₄H₂₈N₂O₉+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate)

A solution of(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-((tert-butoxycarbonyl)amino)propanoate) (2.05 g, 2.70 mmol), inmethylene chloride (30 mL) was treated with trifluoroacetic acid (3 mL)and the mixture was stirred at room temperature for 2 h. After thistime, LC-MS analysis of the reaction mixture showed cleavage of the Bocprotecting groups. N,N-Diisopropylethylamine was added slowly until thereaction mixture tested basic by pH paper analysis (˜5 mL of baseadded). The mixture was treated with (S)-2,5-dioxopyrrolidin-1-yl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (2.15 g, 7.93 mmol) inone portion and stirred at room temperature for 2 h. After this time,the mixture was diluted with ethyl acetate and washed with water andbrine. The organic extracts were dried over sodium sulfate, filtered,and concentrated. The residue was purified by reversed phase columnchromatography (150 g C18 column, 5-100% acetonitrile/water) to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate)(1.20 g, 51%): ESI MS m/z 870 [C₄₃H₅₉N₃O₁₄Si+H]⁺.

Preparation of(2S,2′S)-4,4′-(((((4R,4aS,7aR,12bS)-9-Hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(3-oxopropane-3,1-diyl))bis(azanediyl))bis(2-hydroxy-4-oxobutanoicacid) trifluoroacetic acid salt

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butyldimethylsilyl)oxy)-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diylbis(3-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetamido)propanoate)(1.10 g, 1.26 mmol) in tetrahydrofuran (25 mL) was treated with water(12 mL) followed by trifluoroacetic acid (8 mL), and the mixture wasstirred at room temperature for 3 h. After this time, the mixture wasconcentrated, and the residue was purified by reversed phase columnchromatography (150 g C18 column, 3-20% acetonitrile/water, with 0.1%trifluoracetic acid) and freeze dried to provide(2S,2′S)-4,4′-(((((4R,4aS,7aR,12bS)-9-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diyl)bis(oxy))bis(3-oxopropane-3,1-diyl))bis(azanediyl))bis(2-hydroxy-4-oxobutanoicacid) trifluoroacetic acid salt (277 mg, 26%): ¹H NMR (300 MHz, DMSO-d₆)δ 12.5 (br s, 2H), 9.51-9.28 (m, 2H), 8.13 (t, J=5.7 Hz, 1H), 8.02 (t,J=5.5 Hz, 1H), 6.72 (d, J=8.2 Hz, 1H), 6.66 (d, J=8.2 Hz, 1H), 5.50 (dd,J=6.6, 1.7 Hz, 1H), 5.06 (s, 1H), 4.78-4.65 (m, 1H), 4.32-4.27 (m, 2H),3.56-3.43 (m, 2H), 3.40-3.15 (m, 6H), 3.08-2.88 (m, 4H), 2.87-2.69 (m,2H), 2.67-2.57 (m, 3H), 2.48-2.30 (m, 4H), 2.08 (d, J=18.8 Hz, 1H), 1.78(d, J=12.9 Hz, 1H), two protons obscured by solvent peaks; ESI MS m/z676 [C₃₁H₃₇N₃O₁₄+H]⁺; HPLC (Method A) 97.2% (AUC), t_(R)=6.32 min.

Preparation of(S)-2-(((S)-3-Acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid

A solution of (S)-1-tert-butyl 4-(2,5-dioxopyrrolidin-1-yl)2-acetoxysuccinate (1.66 g, 5.05 mmol), (S)-mandelic acid (861 mg, 5.66mmol), and 4-dimethylaminopyridine (68 mg, 0.56 mmol) in tetrahydrofuran(30 mL) was treated with pyridine (0.82 mL, 10 mmol) and heated at 50°C. under a nitrogen atmosphere for 64 h. After this time, the reactionmixture was cooled to room temperature and concentrated under reducedpressure. The residue was dissolved in ethyl acetate (50 mL); washedwith aqueous 10% citric acid (2×25 mL), water (25 mL), and brine (25mL); dried over sodium sulfate; filtered; and concentrated under reducedpressure. The crude residue was purified by column chromatography(silica gel, 0-10% methanol/methylene chloride) to provide(S)-2-(((S)-3-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid (849 mg, 46%) as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 13.31(s, 1H), 7.47-7.40 (m, 5H), 5.88 (s, 1H), 5.23 (dd, J=8.7, 4.2 Hz, 1H),3.05 (dd, J=16.8, 4.2 Hz, 1H), 2.94 (dd, J=16.8, 8.7 Hz, 1H), 2.05 (s,3H), 1.38 (s, 9H); ESI MS m/z 731 [(2×C₁₈H₂₂O₈)−H]⁻.

Preparation of (S)-1-tert-Butyl4-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate

A solution of(S)-2-(((S)-3-acetoxy-4-(tert-butoxy)-4-oxobutanoyl)oxy)-2-phenylaceticacid (845 mg, 2.31 mmol) in tetrahydrofuran (23 mL) was treated withN-hydroxysuccinimide (292 mg, 2.54 mmol) andN,N′-dicyclohexylcarbodiimide (541 mg, 2.62 mmol) and stirred under anitrogen atmosphere for 16 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether, and the combined filtrate and washings wereconcentrated under reduced pressure to provide (S)-1-tert-butyl4-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate (1.20 g, quantitative) as a white semi-solid: ¹H NMR(300 MHz, DMSO-d₆) δ 7.59-7.56 (m, 2H), 7.50-7.47 (m, 3H), 6.57 (s, 1H),5.22 (dd, J=8.1, 4.5 Hz, 1H), 3.10 (dd, J=16.8, 4.5 Hz, 1H), 3.00 (dd,J=16.8, 8.4 Hz, 1H), 2.78 (br s, 4H), 2.04 (s, 3H), 1.37 (s, 9H).

Preparation of(S)-4-((S)-2-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)1-tert-butyl 2-acetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (510 mg, 1.27 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-1-tert-butyl4-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2-acetoxysuccinate (648 mg, 1.40 mmol) in tetrahydrofuran (5 mL). Afteraddition was complete, the mixture was warmed to 0° C. After this time,the reaction mixture was treated with saturated aqueous ammoniumchloride (20 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (40 g silica gel column, 0-20% methanol/methylenechloride, then 50 g C18 column, 10-100% acetonitrile/water) to provide(S)-4-((S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)1-tert-butyl 2-acetoxysuccinate (382 mg, 40%) as a white solid: ESI MSm/z 750 [C₄₀H₄₇NO₁₃+H]⁺.

Preparation of(S)-2-Acetoxy-4-((S)-2-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacidtrifluoroacetic acid salt

A solution of(S)-4-((S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)1-tert-butyl 2-acetoxysuccinate (190 mg, 0.253 mmol) in methylenechloride (5 mL) was treated with trifluoroacetic acid (3 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 2 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 0-100% acetonitrile/water with 0.1% trifluoroacetic acid) andfreeze dried to provide(S)-2-acetoxy-4-((S)-2-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-4-oxobutanoicacid trifluoroacetic acid salt (124 mg, 67%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 13.4 (br s, 1H), 9.28 (s, 1H), 9.14 (br s, 1H),7.59-7.54 (m, 2H), 7.52-7.45 (m, 3H), 6.64 (apparent q, J=8.1 Hz, 2H),6.25 (s, 1H), 6.17 (s, 1H), 5.60 (dd, J=5.7, 2.1 Hz, 1H), 5.31 (dd,J=8.7, 3.9 Hz, 1H), 4.87 (s, 1H), 3.62-3.33 (m, 2H), 3.14-2.96 (m, 4H),2.82 (d, J=4.2 Hz, 3H), 2.64-2.38 (m, 2H), 2.25 (m, 1H), 2.09-2.02 (m,4H), 1.60 (m, 1H); ESI MS m/z 594 [C₃₁H₃₁NO₁₁+H]⁺.

Preparation of(2R,3R)-2,3-Diacetoxy-4-(((R)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid

(R)-Di-tert-butyl 2-hydroxysuccinate (1.60 g, 6.50 mmol),(3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate (1.76 g, 8.12 mmol),pyridine (462 mg, 5.85 mmol), and N,N-dimethylformamide (4 mL) werecombined and stirred at 0° C. under a nitrogen atmosphere for 3 h. Afterthis time, saturated sodium bicarbonate (15 mL) was added, and theresulting aqueous solution was washed with ethyl acetate (10 mL). Theaqueous phase was collected and acidified to pH=3 with 6 N hydrochloricacid, and the mixture was extracted with ethyl acetate (2×20 mL). Thecombined organics were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide(2R,3R)-2,3-diacetoxy-4-(((R)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid (2.28 g, 75%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 5.80 (d,J=2.7 Hz, 1H), 5.75 (d, J=2.4 Hz, 1H), 5.36 (dd, J=7.8, 5.1 Hz, 1H),2.78-2.74 (m, 2H), 2.21 (s, 3H), 2.19 (s, 3H), 1.46 (s, 9H), 1.44 (s,9H), CO₂H proton not observed.

Preparation of (2R,3R)-1-((R)-1,4-Di-tert-butoxy-1,4-dioxobutan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate

A solution of(2R,3R)-2,3-diacetoxy-4-(((R)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)oxy)-4-oxobutanoicacid (2.28 g, 4.93 mmol) in tetrahydrofuran (40 mL) was treated withN-hydroxysuccinimide (624 mg, 5.42 mmol) andN,N′-dicyclohexylcarbodiimide (1.12 g, 5.42 mmol) and stirred under anitrogen atmosphere for 4 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide(2R,3R)-1-((R)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (3.39 g,quantitative) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 6.14 (d,J=3.0 Hz, 1H), 5.88 (d, J=3.0 Hz, 1H), 5.38 (dd, J=8.1, 3.3 Hz, 1H),2.88-2.68 (m, 6H), 2.24 (s, 3H), 2.23 (s, 3H), 1.46 (s, 9H), 1.44 (s,9H).

Preparation(2R,3R)-1-((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-((R)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl) 2,3-diacetoxysuccinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (500 mg, 1.25 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.5 mL, 1.5 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 15 min. The mixture was re-cooled to −45° C. and treated dropwisewith a solution of(2R,3R)-1-((R)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)4-(2,5-dioxopyrrolidin-1-yl) 2,3-diacetoxysuccinate (766 mg, 1.37 mmol)in tetrahydrofuran (5 mL). After addition was complete, the mixture waswarmed to 0° C. After this time, the reaction mixture was treated withsaturated aqueous ammonium chloride (20 mL) and extracted with ethylacetate (2×25 mL). The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude residue waspurified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(2R,3R)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl) 2,3-diacetoxysuccinate(288 mg, 27%) as a white solid: ESI MS m/z 846 [C₄₂H₅₅NO₁₇+H]⁺.

Preparation of(R)-2-(((2R,3R)-2,3-Diacetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacidtrifluoroacetic acid salt

A solution of(2R,3R)-1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)4-((R)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl) 2,3-diacetoxysuccinate(288 mg, 0.340 mmol) in methylene chloride (5.0 mL) was treated withtrifluoroacetic acid (5.0 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(R)-2-(((2R,3R)-2,3-diacetoxy-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-4-oxobutanoyl)oxy)succinicacid trifluoroacetic acid salt (175 mg, 68%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 13.5 (br s, 1H), 12.8 (br s, 1H), 9.36 (s, 1H),9.16 (br s, 1H), 6.65 (apparent q, J=8.1 Hz, 2H), 6.28 (br s, 1H), 5.82(d, J=2.4 Hz, 1H), 5.78 (d, J=2.4 Hz, 1H), 5.54 (dd, J=6.0, 1.8 Hz, 1H),5.35 (dd, J=7.5, 3.9 Hz, 1H), 4.84 (s, 1H), 3.62-3.34 (m, 2H), 3.02 (m,1H), 2.93-2.72 (m, 5H), 2.63-2.40 (m, 3H), 2.27 (m, 1H), 2.22 (s, 3H),2.11 (s, 3H), 2.07 (m, 1H), 1.62 (m, 1H); ESI MS m/z 634[C₂₉H₃₁NO₁₅+H]⁺.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-acetamido-6-((tert-butoxycarbonyl)amino)hexanoate

A solution of (S)-2-acetamido-6-((tert-butoxycarbonyl)amino)hexanoicacid (1.00 g, 3.47 mmol) in tetrahydrofuran (20 mL) was treated withN-hydroxysuccinimide (439 mg, 3.81 mmol) andN,N′-dicyclohexylcarbodiimide (785 mg, 3.81 mmol) and stirred under anitrogen atmosphere for 2 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-2,5-dioxopyrrolidin-1-yl2-acetamido-6-((tert-butoxycarbonyl)amino)hexanoate (1.49 mg) as a whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 6.27 (m, 1H), 4.94 (m, 1H), 4.69 (m,1H), 3.15-3.13 (m, 2H), 2.87 (s, 4H), 2.08 (s, 3H), 2.02-1.83 (m, 2H),1.55-1.22 (m, 4H), 1.45 (s, 9H).

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-acetamido-6-((tert-butoxycarbonyl)amino)hexanamido)propanoyl)oxy)propanoate

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate hydrochloride (121 mg, 0.233 mmol)in tetrahydrofuran (6 mL) was treated with (S)-2,5-dioxopyrrolidin-1-yl2-acetamido-6-((tert-butoxycarbonyl)amino)hexanoate (90 mg, 0.23 mmol)and N,N-diisopropylethylamine (60 mg, 0.47 mmol) at 0° C. and stirredunder a nitrogen atmosphere for 1 h. After this time the reactionmixture was concentrated under reduced pressure. The residue waspurified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride) to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-acetamido-6-((tert-butoxycarbonyl)amino)hexanamido)propanoyl)oxy)propanoate(126 mg, 75%) as a white solid: ESI MS m/z 715 [C₃₆H₅₀N₄O₁₁+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-acetamido-6-aminohexanamido)propanoyl)oxy)propanoatetrifluoroaceticacid salt

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-acetamido-6-((tert-butoxycarbonyl)amino)hexanamido)propanoyl)oxy)propanoate(126 mg, 0.176 mmol) in methylene chloride (3 mL) was treated withtrifluoroacetic acid (3 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-acetamido-6-aminohexanamido)propanoyl)oxy)propanoatetrifluoroacetic acid salt (51 mg, 32%) as a fluffy white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.16 (br s, 1H), 8.05-7.98 (m, 2H),7.64 (br s, 3H), 6.65 (apparent q, J=8.1 Hz, 2H), 6.25 (s, 2H), 5.58(dd, J=5.7, 1.8 Hz, 1H), 5.10 (q, J=7.2 Hz, 1H), 4.96 (s, 1H), 4.15 (m,1H), 3.67-3.27 (m, 4H), 3.11-3.03 (m, 2H), 2.84 (d, J=4.8 Hz, 3H),2.78-2.72 (m, 2H), 2.67-2.46 (m, 2H), 2.29 (m, 1H), 2.06 (m, 1H), 1.84(s, 3H), 1.65-1.25 (m, 11H); ESI MS m/z 615 [C₃₁H₄₂N₄O₉+H]⁺.

Preparation of (4R,5R)-4-((S)-1-(Benzyloxy)-1-oxopropan-2-yl)5-tert-butyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A mixture of(4S,5S)-5-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid (1.00 g, 4.07 mmol), (S)-benzyl 2-hydroxypropanoate (1.20 g, 6.66mmol), and 4-dimethylaminopyridine (150 mg, 1.23 mmol) in methylenechloride (10 mL) was treated with N,N′-dicyclohexylcarbodiimide (1.10 g,5.33 mmol), and the reaction mixture was stirred at ambient temperaturefor 18 h. After this time, the mixture was filtered, and the filtratewas concentrated under reduced pressure. The residue was purified bycolumn chromatography (40 g silica gel column, 0-50% ethylacetate/heptane) to provide(4S,5S)-4-((S)-1-(benzyloxy)-1-oxopropan-2-yl) 5-tert-butyl2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (780 mg, 47%): ¹H NMR (300MHz, CDCl₃) δ 7.39-7.32 (m, 5H), 5.23 (q, J=7.1 Hz, 1H), 5.18 (s, 2H),4.77 (d, J=5.7 Hz, 1H), 4.65 (d, J=5.7 Hz, 1H), 1.56 (d, J=7.1 Hz, 3H),1.52-1.49 (m, 15H).

Preparation of (S)-2-(((4R,5R)-5-(tert-Butoxycarbonyl)-2,2-dmethyl-1,3-dioxolane-4-carbonyl)oxy)propanoic acid

A mixture of (4S,5S)-4-((S)-1-(benzyloxy)-1-oxopropan-2-yl) 5-tert-butyl2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (770 mg, 1.89 mmol) andpalladium (10% on carbon, 200 mg) in ethanol (25 mL) was stirred at roomtemperature under balloon pressure hydrogen for 2 h. After this time,the reaction mixture was purged with nitrogen and filtered throughdiatomaceous earth. The filtrate was concentrated under reduced pressureto provide(S)-2-(((4S,5S)-5-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-4-carbonyl)oxy)propanoicacid: ¹H NMR (300 MHz, CDCl₃) δ 5.20 (q, J=7.0 Hz, 1H), 4.77 (d, J=5.7Hz, 1H), 4.67 (d, J=5.7 Hz, 1H), 1.59 (d, J=7.0 Hz, 3H), 1.53-1.48 (m,15H), CO₂H proton not observed.

Preparation of (4R,5R)-4-tert-Butyl5-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A mixture of(S)-2-(((4S,5S)-5-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-4-carbonyl)oxy)propanoicacid (580 mg, 1.82 mmol) and N-hydroxysuccinimide (230 mg, 2.00 mmol) intetrahydrofuran (15 mL) was treated with N,N′-dicyclohexylcarbodiimide(413 mg, 2.00 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (15 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide (4S,5S)-4-tert-butyl5-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (960 mg, 76%) that was usedwithout purification: ¹H NMR (300 MHz, CDCl₃) δ 5.53 (q, J=7.1 Hz, 1H),4.80 (d, J=5.6 Hz, 1H), 4.70 (d, J=5.6 Hz, 1H), 2.85 (s, 4H), 1.75 (d,J=7.1 Hz, 3H), 1.52-1.49 (m, 15H).

Preparation of(4R,5R)-4-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)5-tert-butyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (600 mg, 1.50 mmol) in tetrahydrofuran (8 mL) was cooled to 0°C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.6 mL, 1.6 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to 0° C. and (4S,5S)-4-tert-butyl5-((S)-1-((2,5-dioxopyrrolidin-1-yl)oxy)-1-oxopropan-2-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (600 mg, 1.45 mmol) wasadded in one portion. The mixture was stirred at 0° C. for 45 min. Afterthis time, the mixture was treated with saturated aqueous ammoniumchloride and extracted with ethyl acetate. The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by reverse phase columnchromatography (50 g C18 column, 5-100% acetonitrile/water) to provide(4R,5R)-4-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)5-tert-butyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (495 mg, 49%):ESI MS m/z 702 [C₃₆H₄₇NO₁₃+H]⁺.

Preparation of(2R,3R)-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-2,3-dihydroxy-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(4R,5R)-4-((S)-1-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)5-tert-butyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (495 mg, 0.706mmol) in methylene chloride (10 mL) was treated with trifluoroaceticacid (2 mL), and the mixture was stirred at room temperature for 1 h.LC-MS analysis of the reaction mixture indicated cleavage of the Boc andtert-butyl protecting groups. Water (0.1 mL) was added, and the mixturewas stirred at ambient temperature for 6 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas purified by reversed phase column chromatography (50 g C18 column,3-20% acetonitrile/water, with 0.1% trifluoracetic acid) and freezedried to provide(2R,3R)-4-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-2,3-dihydroxy-4-oxobutanoicacid trifluoroacetic acid salt (163 mg, 41%): ¹H NMR (300 MHz, DMSO-d₆)δ 12.83 (br s, 1H), 9.30 (br s, 1H), 9.17 (br s, 1H), 6.69 (d, J=8.1 Hz,1H), 6.63 (d, J=8.1 Hz, 1H), 6.27 (s, 1H), 5.60 (dd, J=6.0, 2.0 Hz, 1H),5.18 (q, J=7.0 Hz, 1H), 4.99 (s, 1H), 4.48 (d, J=2.2 Hz, 1H), 4.39 (d.J=2.1 Hz, 1H), 3.63 (d, J=6.3 Hz, 1H), 3.38 (d, J=20.0 Hz, 1H),3.14-3.00 (m, 2H), 2.84 (apparent d, J=4.2 Hz, 3H), 2.70-2.57 (m, 1H),2.44 (dd, J=13.6, 4.9 Hz, 1H), 2.29 (dd, J=17.9, 6.1 Hz, 1H), 2.07 (d,J=17.9 Hz, 1H), 1.63 (d, J=11.3 Hz, 1H), 1.53 (d, J=7.0 Hz, 3H), twoprotons obscured by solvent peaks; ESI MS m/z 506 [C₂₄H₂₇NO₁₁+H]⁺; HPLC(Method A) 94.4% (AUC), t_(R)=6.71 min.

Preparation of (S)-tert-Butyl 2-hydroxypropanoate

A solution of (S)-2-hydroxypropanoic acid (5.0 g, 55 mmol) and aceticacid (1 mL) in dichloromethane (40 mL) was cooled in an ice bath andtreated dropwise with acetyl chloride (4.5 mL, 61 mmol). After additionwas complete, the mixture was stirred at ambient temperature for 16 h.After this time, the mixture was diluted with water (50 mL) andextracted with methylene chloride (2×50 mL). The combined organics werewashed with brine (50 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide (S)-2-acetoxypropanoicacid (6.0 g) as a colorless oil.

(S)-2-acetoxypropanoic acid (6.0 g, 55 mmol), tert-butyl alcohol (8.10g, 110 mmol),N,N-dimethylpyridin-4-amine (2.0 g, 16 mmol) andN,N′-dicyclohexylcarbodiimide (14.7 g, 71.5 mmol) were combined andstirred at ambient temperature for 16 h. After this time, the mixturewas filtered and concentrated under reduced pressure to provide(S)-tert-butyl 2-acetoxypropanoate (12 g) as a colorless oil.

A solution of (S)-tert-butyl 2-acetoxypropanoate (12 g, 55 mmol) inmethanol (40 mL) was cooled in an ice bath and treated with a solutionof potassium carbonate (22.8 g, 165 mmol) in water (40 mL). Afteraddition was complete, the mixture was stirred in an ice bath for 5 h.After this time, the mixture was diluted with water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organics werewashed with brine (50 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (silica gel, 0-30% ethyl acetate/heptanes) toprovide (S)-tert-butyl 2-hydroxypropanoate (1.14 g, 15% in three steps)as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 4.13 (dd, J=6.9, 5.4 Hz,1H), 2.82 (d, J=5.4 Hz, 1H), 1.49 (s, 9H), 1.37 (d, J=6.9 Hz, 3H).

Preparation of (S)-tert-Butyl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate

A solution of (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid(0.66 g, 3.8 mmol) in dichloromethane (20 mL) was treated with(S)-tert-butyl 2-hydroxypropanoate (0.50 g, 3.4mmol),N,N-dimethylpyridin-4-amine (0.13 g, 1.0 mmol) andN,N′-dicyclohexylcarbodiimide (0.85 g, 4.1 mmol). The mixture wasstirred at ambient temperature for 16 h. After this time, the mixturewas filtered and concentrated under reduced pressure. The crude residuewas purified by column chromatography (silica gel, 0-30% ethylacetate/heptanes) to provide (S)-tert-butyl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate (0.22g, 21%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 4.99 (dd, J=14.1,8.4 Hz, 1H), 4.74 (dd, J=6.6, 3.6 Hz, 1H), 3.04 (dd, J=14.1, 3.6 Hz,1H), 2.85 (dd, J=17.4, 8.4 Hz, 1H), 1.62 (s, 3H), 1.55 (s, 3H), 1.47 (d,J=6.2 Hz, 3H), 1.46 (s, 9H).

Preparation of(S)-4-(((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)oxy)-2-hydroxy-4-oxobutanoicacid

A solution of (S)-tert-butyl2-(2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetoxy)propanoate (3.07g, 10.2 mmol), acetic acid (35 mL), and water (15 mL) was heated at 60°C. for 1 h. After this time, the mixture was concentrated under reducedpressure. The residue was diluted with toluene and concentrated underreduced pressure to provide of(S)-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-2-hydroxy-4-oxobutanoicacid (2.99 g, 99%) as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 12.6(s, 1H), 5.51 (s, 1H), 4.82 (dd, J=14.1, 6.9 Hz, 1H), 4.31-4.30 (m, 1H),2.72 (dd, J=15.9, 4.5 Hz, 1H), 2.60 (dd, J=15.9, 7.8 Hz, 1H), 1.40 (s,9H), 1.36 (d, J=7.2 Hz, 3H).

Preparation of (S)-1-Benzyl 4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate

(S)-4-(((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)oxy)-2-hydroxy-4-oxobutanoicacid (0.26 g, 1.0 mmol), benzylalcohol (0.15 g, 1.2mmol),N,N-dimethylpyridin-4-amine (44 mg, 0.30 mmol), andN,N′-dicyclohexylcarbodiimide (0.30 g, 1.2 mmol) were combined andstirred in methylene chloride (10 mL) at ambient temperature for 16 h.After this time, the mixture was filtered and concentrated under reducedpressure to provide to provide (S)-1-benzyl4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl) 2-hydroxysuccinate (0.32 g) asa colorless oil.

(S)-1-Benzyl 4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl) 2-hydroxysuccinate(0.32 g, 0.91 mmol), di-tert-butyl dicarbonate (0.22 g, 1.0 mmol), and4-dimethylaminopyridine (12 mg, 0.098 mmol) were combined and stirred inmethylene chloride (10 mL) at ambient temperature for 3 h. After thistime, the mixture was concentrated under reduced pressure. The cruderesidue was purified by column chromatography (silica gel, 0-30% ethylacetate/heptanes) to provide (S)-1-benzyl4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate (0.21 g, 46% in two steps) as acolorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.32 (m, 5H), 5.41 (dd,J=8.1, 4.5 Hz, 1H), 5.26 (d, J=12 Hz, 1H), 5.14 (d, J=12 Hz, 1H), 4.96(dd, J=14.1, 7.2 Hz, 1H), 2.98-2.94 (m, 2H), 1.46 (s, 9H), 1.45 (s, 9H),1.42 (d, J=7.2 Hz, 3H).

Preparation of (S)-4-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate

A solution of (S)-1-benzyl 4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)2-((tert-butoxycarbonyl)oxy)succinate (0.54 g, 1.2 mmol) in ethylalcohol (8 mL) was treated with palladium on carbon (10%, 0.1 g). Themixture was stirred under a hydrogen atmosphere at ambient temperaturefor 2 h. After this time, the reaction mixture was filtered andconcentrated under reduced pressure to provide(S)-4-(((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoicacid (0.5 g) as a colorless oil.

(S)-4-(((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)oxy)-2-((tert-butoxycarbonyl)oxy)-4-oxobutanoicacid (0.50 g, 1.2 mmol), 1-hydroxypyrrolidine-2,5-dione (0.16 g, 1.4mmol) and N,N′-dicyclohexylcarbodiimide (0.27 g, 1.3 mmol) were combinedand stirred in tetrahydrofuran (10 mL) at ambient temperature for 4 h.After this time, the mixture was filtered and concentrated under reducedpressure to provide (S)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate (0.8g) as a sticky solid, which was used without purification.

Preparation of (S)-4-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (400 mg, 0.996 mmol) in tetrahydrofuran (10 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.2 mL, 1.2 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)oxy)succinate (504mg, 1.10 mmol) in tetrahydrofuran (5 mL). After addition was complete,the mixture was warmed to 0° C. After this time, the reaction mixturewas treated with saturated aqueous ammonium chloride (20 mL) andextracted with ethyl acetate (2×50 mL). The combined organics were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude residue was purified by column chromatography (40 g silica gelcolumn, 0-20% methanol/methylene chloride, then 50 g C18 column, 10-100%acetonitrile/water) to provide(S)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate (37 mg, 5%) as a white solid: ESIMS m/z 746 [C₃₈H₅₁NO₁₄+H]⁺.

Preparation of(S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)propanoicacidtrifluoroacetic acid salt

A solution of (S)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)1-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2-((tert-butoxycarbonyl)oxy)succinate (37 mg, 0.050 mmol) in methylenechloride (3 mL) was treated with trifluoroacetic acid (1 mL) and stirredunder a nitrogen atmosphere at ambient temperature for 1 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by reversed phase column chromatography (50 g C18column, 0-100% acetonitrile/water with 0.1% trifluoroacetic acid) andfreeze dried to provide(S)-2-(((S)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-3-hydroxy-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt (27 mg, 90%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ9.30 (s, 1H), 9.14 (br s, 1H), 6.64 (apparent q,J=8.4 Hz, 2H), 6.24 (br s, 1H), 5.97 (d, J=6.0 Hz, 1H), 5.57 (d, J=3.9Hz, 1H), 5.00-4.93 (m, 2H), 4.53 (m, 1H), 3.41-3.33 (m, 2H), 3.05 (m,1H), 2.89-2.72 (m, 6H), 2.63-2.41 (m, 3H), 2.27 (m, 1H), 2.07 (m, 1H),1.62 (m, 1H), 1.40 (d, J=7.2 Hz, 3H); ESI MS m/z 490 [C₂₄H₂₇NO₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)propanoyl)oxy)propanoate

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate dihydrochloride (121 mg, 0.233 mmol)in tetrahydrofuran (6 mL) was treated with (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)amino)-4-methylpentanoate (63 mg, 0.23 mmol) andN,N-diisopropylethylamine (60 mg, 0.47 mmol) at 0° C. and stirred undera nitrogen atmosphere for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (40 g silica gel column, 0-20% methanol/methylenechloride) to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)propanoyl)oxy)propanoate(76 mg, 54%) as a white solid: ESI MS m/z 658 [C₃₄H₄₇N₃O₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-amino-4-methylpentanamido)propanoyl)oxy)propanoatebis(trifluoroaceticacid salt)

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)propanoyl)oxy)propanoate(76 mg, 0.12 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (2 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-amino-4-methylpentanamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt) (50 mg, 50%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.16 (br s, 1H), 8.62 (t, J=5.4Hz, 1H), 8.09 (br s, 3H), 6.65 (apparent q, J=8.1 Hz, 2H), 6.24 (s, 1H),5.58 (dd, J=6.0, 2.1 Hz, 1H), 5.12 (q, J=6.9 Hz, 1H), 4.96 (s, 1H),3.67-3.27 (m, 4H), 3.05 (m, 1H), 2.84 (d, J=4.8 Hz, 3H), 2.63-2.41 (m,6H), 2.28 (m, 1H), 2.05 (m, 1H), 1.64-1.52 (m, 7H), 0.89 (dd, J=6.0, 2.1Hz, 6H); ESI MS m/z 558 [C₂₉H₃₉N₃O₈+H]⁺.

Preparation of(S)-2-(((S)-2-((tert-Butoxycarbonyl)amino)propanoyl)oxy)propanoic acid

(S)-Lactic acid (944 mg, 10.5 mmol), (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)amino)propanoate (2.50 g, 8.73 mmol),4-(dimethylamino)pyridine (107 mg, 0.873 mmol), pyridine (831 mg, 10.5mmol), and tetrahydrofuran (40 mL) were combined and heated at 75° C.under a nitrogen atmosphere for 24 h. After this time, the solvent wasremoved under reduced pressure, and the residue was partitioned betweenethyl acetate (20 mL) and 10% aqueous citric acid. The organic layer wasseparated and extracted with saturated aqueous sodium bicarbonate (20ml). The aqueous phase was collected and acidified to pH=2 with 6 Nhydrochloric acid, and the mixture was extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine (50 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide(S)-2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoic acid(2.10 g, 92%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 5.19 (t,J=6.9 Hz, 1H), 5.01 (m, 1H), 4.35 (m, 1H), 1.56 (d, J=7.2 Hz, 3H),1.46-1.43 (s, 12H), CO₂H proton not observed.

Preparation of (S)-2,5-Dioxopyrrolidin-1-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate

A solution of(S)-2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoic acid(2.10 g, 8.04 mmol) in tetrahydrofuran (40 mL) was treated withN-hydroxysuccinimide (1.02 g, 8.84 mmol) andN,N′-dicyclohexylcarbodiimide (1.82 g, 8.84 mmol) and stirred under anitrogen atmosphere for 5 h. After this time, the reaction mixture wasfiltered to remove the solid dicyclohexylurea byproduct. The solid waswashed with diethyl ether (100 mL), and the combined filtrate andwashings were concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide (S)-2,5-dioxopyrrolidin-1-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (2.73 g)as a white powder: ¹H NMR (300 MHz, CDCl₃) δ 5.46 (m, 1H), 5.02 (m, 1H),4.38 (m, 1H), 2.82 (s, 4H), 1.69 (d, J=6.6 Hz, 3H), 1.46-1.42 (s, 12H).

Preparation of(S)-(4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (1.50 g, 3.74 mmol) in tetrahydrofuran (30 mL) was cooled inan ice bath and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (4.5 mL, 4.5 mmol). Afteraddition was complete, the mixture was stirred at 0° C. for 1 h. Themixture was re-cooled to −45° C. and treated dropwise with a solution of(S)-2,5-dioxopyrrolidin-1-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (1.47 g,4.11 mmol) in tetrahydrofuran (15 mL). After addition was complete, themixture was warmed to 0° C. After this time, the reaction mixture wastreated with saturated aqueous ammonium chloride (20 mL) and extractedwith ethyl acetate (2×50 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue was purified by column chromatography (40 g, silica gel,0-20% methanol/methylene chloride, then 50 g, C18, 10-100%acetonitrile/water) to provide(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1 H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (1.04 g,43%) as a white solid: ESI MS m/z 645 [C₃₃H₄₄N₂O₁₁+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-aminopropanoyl)oxy)propanoate dihydrochloride

A solution of(S)-(4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((tert-butoxycarbonyl)amino)propanoyl)oxy)propanoate (150 mg,0.233 mmol) was treated with a 4.0 M solution of hydrogen chloride in1,4-dioxane (5 mL) and stirred under a nitrogen atmosphere at ambienttemperature for 1 h. After this time, the reaction mixture concentratedunder vacuum to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-aminopropanoyl)oxy)propanoatedihydrochloride (121 mg, 100%) asa white solid: ESI MS m/z 445 [C₂₃H₂₈N₂O₇+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-2-acetamido-6-((tert-butoxycarbonyl)amino)hexanamido)propanoyl)oxy)propanoate

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-aminopropanoyl)oxy)propanoate hydrochloride (121 mg, 0.233mmol) in tetrahydrofuran (6 mL) was treated with(S)-2,5-dioxopyrrolidin-1-yl2-acetamido-6-((tert-butoxycarbonyl)amino)hexanoate (90 mg, 0.23 mmol)and N,N-diisopropylethylamine (60 mg, 0.47 mmol) at 0° C. and stirredunder a nitrogen atmosphere for 1 h. After this time, the reactionmixture was concentrated under reduced pressure. The residue waspurified by reversed phase column chromatography (50 g C18 column,10-100% acetonitrile/water) to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-2-acetamido-6-((tert-butoxycarbonyl)amino)hexanamido)propanoyl)oxy)propanoate(34 mg, 20%) as a white solid: ESI MS m/z 715 [C₃₆H₅₀N₄O₁₁+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-2-acetamido-6-aminohexanamido)propanoyl)oxy)propanoatebis(trifluoroaceticacid salt)

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-2-acetamido-6-((tert-butoxycarbonyl)amino)hexanamido)propanoyl)oxy)propanoate(34 mg, 0.048 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-2-acetamido-6-aminohexanamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt)(12 mg, 24%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 9.16 (br s, 1H), 8.43 (d, J=6.3Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.61 (br s, 3H), 6.65 (apparent q,J=8.1 Hz, 2H), 6.22 (s, 1H), 5.57 (dd, J=6.0, 2.1 Hz, 1H), 5.14 (q,J=6.9 Hz, 1H), 4.35-4.30 (m, 3H), 3.46-3.33 (m, 2H), 3.11 (m, 1H), 2.84(d, J=5.1 Hz, 3H), 2.74-2.41 (m, 3H), 2.27 (m, 1H), 2.07 (m, 1H), 1.84(s, 3H), 1.64-1.32 (m, 14H); ESI MS m/z 615 [C₃₁H₄₂N₄O₉+H]⁺.

Preparation of (S)-2-(((4R,5R)-5-(tert-Butoxycarbonyl)-2,2-dmethyl-1,3-dioxolane-4-carbonyl)oxy)-2-phenylacetic acid

A mixture of (4R,5R)-4-tert-butyl 5-(2,5-dioxopyrrolidin-1-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (1.42 g, 4.15 mmol),(S)-2-hydroxy-2-phenylacetic acid (900 mg, 5.92 mmol), pyridine (0.45mL, 5.60 mmol), and 4-dimethylaminopyridine (60 mg, 0.49 mmol) intetrahydrofuran (25 mL) was stirred at reflux for 18 h. After this time,the mixture was cooled to room temperature, partially concentrated underreduced pressure, diluted with ethyl acetate, washed with 10% citricacid and brine, and concentrated under reduced pressure. The residue waspurified by reversed phase column chromatography (50 g C18 column,5-100% acetonitrile/water) and freeze dried to provide(S)-2-(((4R,5R)-5-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-4-carbonyl)oxy)-2-phenylaceticacid (425 mg, 27%): ¹H NMR (300 MHz, CDCl₃) δ 7.53-7.46 (m, 2H),7.43-7.35 (m, 3H), 6.02 (s, 1H), 4.85 (d, J=5.8 Hz, 1H), 4.67 (d, J=5.8Hz, 1H), 1.52 (s, 3H), 1.51 (s, 3H), 1.42 (s, 9H), CO₂H proton notobserved.

Preparation of (4R,5R)-4-tert-Butyl5-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A mixture of(S)-2-(((4R,5R)-5-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-4-carbonyl)oxy)-2-phenylaceticacid (425 mg, 1.12 mmol) and N-hydroxysuccinimide (142 mg, 1.23 mmol) intetrahydrofuran (10 mL) was treated with N,N′-dicyclohexylcarbodiimide(255 mg, 1.23 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (10 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide (4R,5R)-4-tert-butyl5-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (600 mg) that was usedwithout purification: ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.52 (m, 2H),7.48-7.43 (m, 3H), 6.43 (s, 1H), 4.86 (d, J=5.6 Hz, 1H), 4.67 (d, J=5.6Hz, 1H), 2.81 (s, 4H), 1.50 (s, 6H), 1.43 (s, 9H).

Preparation of(4R,5R)-4-((S)-2-(((4R,4aS,7aR,12bS)-9-((tert-Butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)5-tert-butyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (450 mg, 1.12 mmol) in tetrahydrofuran (8 mL) was cooled to 0°C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.2 mL, 1.2 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to 0° C., and (4R,5R)-4-tert-butyl5-((S)-2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxo-1-phenylethyl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (535 mg, 1.12 mmol) wasadded in one portion. The mixture was stirred at 0° C. for 45 min. Afterthis time, the mixture was treated with saturated aqueous ammoniumchloride and extracted with ethyl acetate. The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 5-100% acetonitrile/water) to provide(4R,5R)-4-((S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)5-tert-butyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (425 mg, 51%):ESI MS m/z 764 [C₄₁H₄₉NO₁₃+H]⁺.

Preparation of(2R,3R)-4-((S)-2-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-2,3-dihydroxy-4-oxobutanoicacid trifluoroacetic acid salt

A solution of(4R,5R)-4-((S)-2-(((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethyl)5-tert-butyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (425 mg, 0.556mmol), in methylene chloride (10 mL) was treated with trifluoroaceticacid (2 mL), and the mixture was stirred at room temperature for 1 h.LC-MS analysis of the reaction mixture indicated cleavage of the Boc andtert-butyl protecting groups. Water (0.1 mL) was added, and the mixturewas stirred at ambient temperature for 7 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas purified by reversed phase column chromatography (50 g C18 column,3-20% acetonitrile/water, with 0.1% trifluoracetic acid) and freezedried to provide(2R,3R)-4-((S)-2-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2-oxo-1-phenylethoxy)-2,3-dihydroxy-4-oxobutanoicacid trifluoroacetic acid salt (186 mg, 47%): ¹H NMR (300 MHz, DMSO-d₆)δ 12.86 (br s, 1H), 9.30 (br s, 1H), 9.14 (br s, 1H), 7.62-7.56 (m, 2H),7.50-7.43 (d, 3H), 6.68 (d, J=8.1 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 6.27(s, 1H), 6.16 (s, 1H), 5.61 (dd, J=6.0, 2.0 Hz, 1H), 4.90 (s, 1H), 4.58(d, J=2.0 Hz, 1H), 4.38 (d, J=2.3 Hz, 1H), 3.61 (d, J=6.2 Hz, 1H), 3.37(d, J=19.8 Hz, 1H), 3.13-3.00 (m, 2H), 2.83 (d, J=4.3 Hz, 3H), 2.68-2.56(m, 1H), 2.41 (dd, J=13.0, 4.7 Hz, 1H), 2.26 (dd, J=18.0, 6.2 Hz, 1H),2.07 (d, J=18.0 Hz, 1H), 1.60 (d, J=10.8 Hz, 1H), two protons obscuredby solvent peaks; ESI MS m/z 568 [C₂₉H₂₉NO₁₁+H]⁺; HPLC (Method A) 98.9%(AUC), t_(R)=7.65 min.

Preparation of(4R,5R)-5-((((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)oxy)carbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid

A mixture of (4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylic acid(770 mg, 4.05 mmol), (S)-tert-butyl 2-hydroxypropanoate (595 mg, 4.08mmol), and 4-dimethylaminopyridine (150 mg, 1.23 mmol) in methylenechloride (12 mL) was treated with N,N′-dicyclohexylcarbodiimide (920 mg,4.46 mmol), and the reaction mixture was stirred at ambient temperaturefor 18 h. After this time, the mixture was filtered, and the filtratewas concentrated under reduced pressure. The residue was dissolved inethyl acetate, washed with 2 N hydrochloric acid, and then extractedwith saturated sodium bicarbonate. The aqueous layer was collected,carefully treated with 6N hydrochloric acid until acidic by pH paperanalysis, and then extracted with ethyl acetate. The organic extractswere dried over sodium sulfate, filtered, and concentrated to provide(4R,5R)-5-((((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)carbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid (780 mg, 61%): ¹H NMR (300 MHz, CDCl₃) δ 5.05 (q, J=7.1 Hz, 1H),4.91 (d, J=5.4 Hz, 1H), 4.87 (d, J=5.4 Hz, 1H), 1.54 (s, 6H), 1.53 (d,J=7.1 Hz, 3H), 1.47 (s, 9H), CO₂H proton not observed.

Preparation of (4R,5R)-4-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)5-(2,5-dioxopyrrolidin-1-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A mixture of(4R,5R)-5-((((S)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)carbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid (780 mg, 2.45 mmol) and N-hydroxysuccinimide (310 mg, 2.69 mmol) intetrahydrofuran (20 mL) was treated with N,N-dicyclohexylcarbodiimide(555 mg, 2.69 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (15 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide(4R,5R)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)5-(2,5-dioxopyrrolidin-1-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (1.0 g) that was usedwithout purification: ¹H NMR (300 MHz, CDCl₃) δ 5.22 (d, J=4.7 Hz, 1H),5.08 (d, J=4.7 Hz, 1H), 5.03 (q, J=7.1 Hz, 1H), 2.87 (s, 4H), 1.57 (s,3H), 1.56 (s, 3H), 1.53 (d, J=7.1 Hz, 3H), 1.47 (s, 9H).

Preparation of (4R,5R)-4-((S)-1-(tert-Butoxy)-1-oxopropan-2-yl)5-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (480 mg, 1.19 mmol) in tetrahydrofuran (8 mL) was cooled to 0°C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (1.3 mL, 1.3 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to 0° C., and(4R,5R)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)5-(2,5-dioxopyrrolidin-1-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (500 mg, 1.20 mmol) wasadded in one portion. The mixture was stirred at 0° C. for 45 min. Afterthis time, the mixture was treated with saturated aqueous ammoniumchloride and extracted with ethyl acetate. The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 5-100% acetonitrile/water) to provide(4R,5R)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)5-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (289 mg, 35%): ESI MS m/z702 [C₃₆H₄₇NO₁₃+H]⁺.

Preparation of(S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt

A solution of (4R,5R)-4-((S)-1-(tert-butoxy)-1-oxopropan-2-yl)5-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (288 mg, 0.410 mmol) inmethylene chloride (8 mL) was treated with trifluoroacetic acid (1.5mL), and the mixture was stirred at room temperature for 1 h. LC-MSanalysis of the reaction mixture indicated cleavage of the Boc andt-butyl protecting groups. Water (0.1 mL) was added, and the mixture wasstirred at ambient temperature for 6 h. After this time, the reactionmixture was concentrated under reduced pressure. The residue waspurified by reversed phase column chromatography (50 g C18 column, 3-20%acetonitrile/water, with 0.1% trifluoracetic acid) and freeze dried toprovide(S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)propanoicacid trifluoroacetic acid salt (160 mg, 61%): ¹H NMR (300 MHz, DMSO-d₆)δ 13.4 (br s, 1H), 9.32 (s, 1H), 9.17 (br s, 1H), 6.69 (d, J=8.2 Hz,1H), 6.63 (d, J=8.2 Hz, 1H), 6.26 (s, 1H), 5.83 (br s, 2H), 5.56 (dd,J=5.9, 1.9 Hz, 1H), 5.03 (s, 1H), 4.99 (q, J=7.1 Hz, 1H), 4.62 (s, 1H),4.56 (s, 1H), 3.62 (d, J=6.1 Hz, 1H), 3.38 (d, J=20.0 Hz, 1H), 3.13-3.01(m, 2H), 2.84 (apparent d, J=4.1 Hz, 3H), 2.71-2.58 (m, 1H), 2.45 (dd,J=14.1, 5.6 Hz, 1H), 2.30 (dd, J=18.0, 6.1 Hz, 1H), 2.06 (d, J=18.0 Hz,1H), 1.64 (d, J=10.7 Hz, 1H), 1.43 (d, J=7.1 Hz, 3H); ESI MS m/z 506[C₂₄H₂₇NO₁₁+H]⁺; HPLC (Method A) 98.7% (AUC), t_(R)=6.42 min.

Preparation of (S)-tert-Butyl2-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)carbamoyl)pyrrolidine-1-carboxylate

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate dihydrochloride (121 mg, 0.233 mmol)in tetrahydrofuran (6 mL) was treated with (S)-1-tert-butyl2-(2,5-dioxopyrrolidin-1-yl) pyrrolidine-1,2-dicarboxylate (87 mg, 0.28mmol) and N,N-diisopropylethylamine (60 mg, 0.47 mmol) at 0° C. andstirred under a nitrogen atmosphere for 1 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas purified by column chromatography (40 g silica gel column, 0-20%methanol/methylene chloride) to provide (S)-tert-butyl2-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)carbamoyl)pyrrolidine-1-carboxylate(81 mg, 54%) as a white solid: ESI MS m/z 642 [C₃₃H₄₃N₃O₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-pyrrolidine-2-carboxamido)propanoyl)oxy)propanoatebis(trifluoroaceticacid salt)

A solution of (S)-tert-butyl2-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)carbamoyl)pyrrolidine-1-carboxylate(81 mg, 0.13 mmol) in methylene chloride (2 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-pyrrolidine-2-carboxamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt) (55 mg, 53%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 9.19 (br s, 2H), 8.61 (t, J=5.7Hz, 1H), 8.54 (br s, 1H), 6.66 (apparent q, J=8.1 Hz, 2H), 6.25 (s, 1H),5.58 (dd, J=6.0, 2.1 Hz, 1H), 5.12 (q, J=6.9 Hz, 1H), 4.96 (s, 1H),4.13-3.03 (m, 10H), 2.84 (d, J=4.5 Hz, 3H), 2.64-2.19 (m, 5H), 2.05 (m,1H), 1.92-1.77 (m, 3H), 1.62 (m, 1H), 1.53 (d, J=7.2 Hz, 3H); ESI MS m/z542 [C₂₈H₃₅N₃O₈+H]⁺.

Preparation of(4R,5R)-5-(((S)-2-(tert-Butoxy)-2-oxo-1-phenylethoxy)carbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid

A mixture of (4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylic acid(765 mg, 4.03 mmol), (S)-tert-butyl 2-hydroxy-2-phenylacetate(enantiomeric ratio=−6:4, 843 mg, 4.05 mmol), and4-dimethylaminopyridine (150 mg, 1.23 mmol) in methylene chloride (12mL) was treated with N,N′-dicyclohexylcarbodiimide (920 mg, 4.46 mmol),and the reaction mixture was stirred at ambient temperature for 18 h.After this time, the mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate, washed with 2 N hydrochloric acid, and then extracted withsaturated sodium bicarbonate. The aqueous layer was collected, carefullytreated with 6N hydrochloric acid until acidic by pH paper analysis, andthen extracted with ethyl acetate. The organic extracts were dried oversodium sulfate, filtered, and concentrated to provide(4R,5R)-5-(((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)carbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid (550 mg, 36%) as a ˜6:4 mixture of diastereomers: ¹H NMR (300 MHz,CDCl₃) δ 7.50-7.42 (m, 2H), 7.42-7.34 (m, 3H), 5.92 (s, 0.4H), 5.89 (s,0.6H), 5.08 (d, J=5.5 Hz, 0.4H), 4.98-4.91 (m, 1.6H), 1.58-1.51 (m, 6H),1.40 (s, 9H), CO₂H proton not observed.

Preparation of (4R,5R)-4-((S)-2-(tert-Butoxy)-2-oxo-1-phenylethyl)5-(2,5-dioxopyrrolidin-1-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A mixture of(4R,5R)-5-(((S)-2-(tert-butoxy)-2-oxo-1-phenylethoxy)carbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid (550 mg, 1.45 mmol) and N-hydroxysuccinimide (185 mg, 1.61 mmol) intetrahydrofuran (10 mL) was treated with N,N′-dicyclohexylcarbodiimide(330 mg, 1.60 mmol), and the reaction mixture was stirred at ambienttemperature for 4 h. After this time, diethyl ether (10 mL) was added,and the mixture was filtered. The filtrate was concentrated underreduced pressure to provide(4R,5R)-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)5-(2,5-dioxopyrrolidin-1-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (700 mg) that was usedwithout purification: ¹H NMR (300 MHz, CDCl₃, Mixture of diastereomers)δ 7.49-7.43 (m, 2H), 7.43-7.34 (m, 3H), 5.89 (s, 0.4H), 5.88 (s, 0.6H),5.46 (d, J=4.3 Hz, 0.4H), 5.25 (d, J=4.3 Hz, 0.6H), 5.17 (d, J=4.3 Hz,1H), 2.85 (s, 4H), 1.59-1.54 (m, 6H), 1.40 (s, 9H).

Preparation of (4R,5R)-4-((S)-2-(tert-Butoxy)-2-oxo-1-phenylethyl)5-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate

A solution of tert-butyl((4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)carbonate (310 mg, 0.77 mmol) in tetrahydrofuran (5 mL) was cooled to 0°C. and treated dropwise with a 1.0 M solution of lithiumbis(trimethylsilyl)amidein tetrahydrofuran (0.8 mL, 0.8 mmol). Afteraddition was complete, the mixture was stirred at ambient temperaturefor 10 min. The mixture was re-cooled to 0° C., and(4R,5R)-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)5-(2,5-dioxopyrrolidin-1-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (343 mg, 0.72 mmol) wasadded in one portion. The mixture was stirred at 0° C. for 45 min. Afterthis time, the mixture was treated with saturated aqueous ammoniumchloride and extracted with ethyl acetate. The combined organics weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by reversed phase columnchromatography (50 g C18 column, 5-100% acetonitrile/water) to provide(4R,5R)-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)5-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (270 mg, 49%, ˜6:4 mixtureof diastereomers): ESI MS m/z 764 [C₄₁H₄₉NO₁₃+H]⁺.

Preparation of(S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt and(R)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt

A solution of (4R,5R)-4-((S)-2-(tert-butoxy)-2-oxo-1-phenylethyl)5-((4R,4aS,7aR,12bS)-9-((tert-butoxycarbonyl)oxy)-4a-hydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (270 mg, 0.35 mmol) inmethylene chloride (8 mL) was treated with trifluoroacetic acid (1.5mL), and the mixture was stirred at room temperature for 1 h. LC-MSanalysis of the reaction mixture indicated cleavage of the Boc andtert-butyl protecting groups. Water (0.1 mL) was added, and the mixturewas stirred at ambient temperature for 3 h. After this time, thereaction mixture was concentrated under reduced pressure. The residuewas purified by reversed phase column chromatography (50 g C18 column,3-20% acetonitrile/water, with 0.1% trifluoracetic acid) and freezedried to provide of(S)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt and(R)-2-(((2R,3R)-4-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-2,3-dihydroxy-4-oxobutanoyl)oxy)-2-phenylaceticacid trifluoroacetic acid salt.

Isomer A (86 mg, 33%): ¹H NMR (300 MHz, DMSO-d₆) δ 13.38 (br s, 1H),9.32 (s, 1H), 9.17 (br s, 1H), 7.54-7.47 (m, 2H), 7.47-7.39 (m, 3H),6.69 (d, J=8.2 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 6.26 (s, 1H), 5.99-5.80(m, 3H), 5.54 (dd, J=6.1, 2.0 Hz, 1H), 5.02 (s, 1H), 4.67 (d, J=1.6 Hz,1H), 4.59 (d, J=1.5 Hz, 1H), 3.62 (d, J=7.1 Hz, 1H), 3.38 (d, J=18.7 Hz,1H), 3.13-3.00 (m, 2H), 2.84 (s, 3H), 2.70-2.57 (m, 1H), 2.43 (dd,J=14.2, 5.5 Hz, 1H), 2.28 (dd, J=17.5, 6.2 Hz, 1H), 2.05 (d, J=17.7 Hz,1H), 1.63 (d, J=10.5 Hz, 1H); ESI MS m/z 568 [C₂₉H₂₉NO₁₁+H]⁺; HPLC(Method A) 95.2% (AUC), t_(R)=7.79 min.

Isomer B (49 mg, 18%): ¹H NMR (300 MHz, DMSO-d₆) δ 13.28 (br s, 1H),9.32 (s, 1H), 9.15 (br s, 1H), 7.56-7.47 (m, 2H), 7.47-7.37 (m, 3H),6.68 (d, J=8.2 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 6.29 (br s, 1H),5.94-5.89 (m, 3H), 5.56-5.35 (m, 1H), 5.03 (s, 1H), 4.70 (s, 1H), 4.64(dd, J=8.0, 2.4 Hz, 1H), 3.61 (d, J=5.6 Hz, 1H), 3.41-3.38 (m, 1H),3.14-2.99 (m, 2H), 2.83 (s, 3H), 2.71-2.58 (m, 1H), 2.47-2.38 (m, 1H),2.27 (dd, J=17.4, 6.5 Hz, 1H), 2.05 (d, J=18.0 Hz, 1H), 1.63 (d, J=12.8Hz, 1H); ESI MS m/z 568 [C₂₉H₂₉NO₁₁+H]⁺; HPLC (Method A) 98.7% (AUC),t_(R)=7.96 min.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)propanoyl)oxy)propanoate

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-aminopropanoyl)oxy)propanoate hydrochloride (121 mg, 0.233mmol) in tetrahydrofuran (6 mL) was treated with(S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)amino)-4-methylpentanoate (92 mg, 0.280 mmol)and diisopropylethylamine (75 mg, 0.583 mmol) at 0° C. and stirred undera nitrogen atmosphere for 1 h. After this time the reaction mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (50 g, C18, 10-100% acetonitrile/water) to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)propanoyl)oxy)propanoate(77 mg, 50%) as a white solid: ESI MS m/z 658 [C₃₄H₄₇N₃O₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-2-amino-4-methylpentanamido)propanoyl)oxy)propanoatebis(trifluoroaceticacid salt)

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)propanoyl)oxy)propanoate(77 mg, 0.117 mmol) in methylene chloride (3 mL) was treated withtrifluoroacetic acid (2 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-2-amino-4-methylpentanamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt)(48 mg, 48%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 9.15 (br s, 1H), 8.93 (d, J=6.9Hz, 1H), 8.13 (br s, 3H), 6.65 (apparent q, J=8.1 Hz, 2H), 6.24 (s, 1H),5.58 (dd, J=6.0, 2.1 Hz, 1H), 5.19 (q, J=6.9 Hz, 1H), 4.95 (s, 1H), 4.47(m, 1H), 3.75 (m, 1H), 3.64-3.52 (m, 2H), 3.05 (m, 1H), 2.84 (d, J=4.5Hz, 3H), 2.73-2.41 (m, 3H), 2.27 (m, 1H), 2.07 (m, 1H), 1.73-1.51 (m,7H), 1.41 (d, J=7.5 Hz, 3H), 0.91 (t, J=6.6 Hz, 6H); ESI MS m/z 558[C₂₉H₃₉N₃O₈+H]⁺.

Preparation of (S)-tert-Butyl4-((tert-butoxycarbonyl)amino)-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoate

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate dihydrochloride (121 mg, 0.233 mmol)in tetrahydrofuran (6 mL) was treated with (S)-5-tert-butyl1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)amino)pentanedioate(112 mg, 0.280 mmol) and N,N-diisopropylethylamine (75 mg, 0.58 mmol) at0° C. and stirred under a nitrogen atmosphere for 1 h. After this timethe reaction mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography (40 g, silica gel, 0-20%methanol/methylene chloride) to (S)-tert-butyl4-((tert-butoxycarbonyl)amino)-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoate(91 mg, 53%) as a white solid: ESI MS m/z 730 [C₃₇H₅₁N₃O₁₂+H]⁺.

Preparation of(S)-4-Amino-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoicacid bis(trifluoroacetic acid salt)

A solution of (S)-tert-butyl4-((tert-butoxycarbonyl)amino)-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoate(91 mg, 0.13 mmol) in methylene chloride (3 mL) was treated withtrifluoroacetic acid (2 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-4-amino-5-((3-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-3-oxopropyl)amino)-5-oxopentanoicacid bis(trifluoroacetic acid salt)(44 mg, 42%) as a fluffy white solid:¹H NMR (300 MHz, DMSO-d₆) δ 12.35 (br s, 1H), 9.32 (s, 1H), 9.17 (br s,1H), 8.61 (t, J=5.4 Hz, 1H), 8.14 (br s, 3H), 6.66 (apparent q, J=8.1Hz, 2H), 6.26 (s, 1H), 5.58 (dd, J=6.0, 2.1 Hz, 1H), 5.11 (q, J=7.2 Hz,1H), 4.96 (s, 1H), 3.74 (m, 1H), 3.67-3.27 (m, 4H), 3.06 (m, 1H), 2.84(s, 3H), 2.63-2.41 (m, 5H), 2.32-2.26 (m, 3H), 2.05 (m, 1H), 1.96-1.88(m, 2H), 1.62 (m, 1H), 1.53 (d, J=7.2 Hz, 3H); ESI MS m/z 574[C₂₈H₃N₃O₁₀+H]⁺.

Preparation of (S)-tert-Butyl2-(((S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-aminopropanoyl)oxy)propanoate hydrochloride (121 mg, 0.233mmol) in tetrahydrofuran (6 mL) was treated with (S)-1-tert-butyl2-(2,5-dioxopyrrolidin-1-yl) pyrrolidine-1,2-dicarboxylate (87 mg, 0.28mmol) and diisopropylethylamine (75 mg, 0.58 mmol) at 0° C. and stirredunder a nitrogen atmosphere for 1 h. After this time the reactionmixture was concentrated under reduced pressure. The residue waspurified by column chromatography (50 g, C18, 10-100%acetonitrile/water) to provide (S)-tert-butyl2-(((S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate(59 mg, 39%) as a white solid: ESI MS m/z 642 [C₃₃H₄₃N₃O₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-pyrrolidine-2-carboxamido)propanoyl)oxy)propanoatebis(trifluoroaceticacid salt)

A solution of (S)-tert-butyl2-(((S)-1-(((S)-1-(((4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)oxy)-1-oxopropan-2-yl)oxy)-1-oxopropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate(59 mg, 0.092 mmol) in methylene chloride (3 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-(((S)-2-((S)-pyrrolidine-2-carboxamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt)(25 mg, 32%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 9.25 (br s, 1H), 9.17 (br s, 1H),8.97 (d, J=6.6 Hz, 1H), 8.56 (brs, 1H), 6.66 (apparent q, J=8.1 Hz, 2H),6.25 (s, 1H), 5.58 (dd, J=6.0, 2.4 Hz, 1H), 5.18 (q, J=6.9 Hz, 1H), 4.95(s, 1H), 4.44 (m, 1H), 4.21 (m, 1H), 3.67-3.03 (m, 4H), 2.84 (d, J=4.5Hz, 3H), 2.72-2.41 (m, 3H), 2.31-2.27 (m, 2H), 2.07 (m, 1H), 1.91-1.84(m, 3H), 1.62 (m, 1H), 1.54 (d, J=7.2 Hz, 3H), 1.41 (d, J=7.2 Hz, 3H);ESI MS m/z 542 [C₂₈H₃₅N₃O₈+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)propanoyl)oxy)propanoate

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-aminopropanoyl)oxy)propanoate dihydrochloride (121 mg, 0.233 mmol)in tetrahydrofuran (6 mL) was treated with (S)-2,5-dioxopyrrolidin-1-yl2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate (98 mg, 0.28 mmol) andN,N-diisopropylethylamine (75 mg, 0.58 mmol) at 0° C. and stirred undera nitrogen atmosphere for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (40 g silica gel column, 0-20% methanol/methylenechloride) to provide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)propanoyl)oxy)propanoate(45 mg, 28%) as a white solid: ESI MS m/z 692 [C₃₇H₄₅N₃O₁₀+H]⁺.

Preparation of(S)-(4R,4aS,7aR,12bS)-4a,9-Dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-amino-3-phenylpropanamido)propanoyl)oxy)propanoatebis(trifluoroaceticacid salt)

A solution of(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)propanoyl)oxy)propanoate(45 mg, 0.066 mmol) in methylene chloride (3 mL) was treated withtrifluoroacetic acid (1 mL) and stirred under a nitrogen atmosphere atambient temperature for 1 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The residue was purified byreversed phase column chromatography (50 g C18 column, 0-100%acetonitrile/water with 0.1% trifluoroacetic acid) and freeze dried toprovide(S)-(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl2-((3-((S)-2-amino-3-phenylpropanamido)propanoyl)oxy)propanoatebis(trifluoroacetic acid salt)(40 mg, 70%) as a fluffy white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 9.16 (br s, 1H), 8.49 (t, J=5.4Hz, 1H), 8.19 (br s, 3H), 7.37-7.24 (m, 5H), 6.65 (apparent q, J=8.1 Hz,2H), 6.25 (s, 1H), 5.57 (dd, J=5.7, 1.8 Hz, 1H), 5.08 (q, J=6.9 Hz, 1H),3.94 (m, 1H), 3.64-3.16 (m, 6H), 3.11-2.92 (m, 4H), 2.84 (d, J=3.3 Hz,3H), 2.73-2.24 (m, 3H), 2.28 (m, 1H), 2.05 (m, 1H), 1.61 (m, 1H), 1.53(d, J=7.2 Hz, 3H); ESI MS m/z 592 [C₃₂H₃₇N₃O₈+H]⁺.

Test Preparation, Procedures, and Analysis

Animal studies were conducted on Rattus norvegicus, specifically of theSprague Dawley strain. Three male Sprague Dawley rats per test articlewere jugular vein cannulated (JVC) for blood collection. The ratsweighed approximately 225-250 g at treatment. The rats were allowed aminimum of 2 day acclimation period and were fasted approximately 16-20hours before dosing. Fasting continued until 4 hours post-dose.

The dosing formulations were prepared on the day of dosing. The testarticle concentration was equivalent to 2 mg/mL oxymorphone HCl or 10mg/mL oxycodone HCl. For test articles that were provided as salt forms,the dosing vehicle was 0.5% methylcellulose in water. For test articlesthat were provided as free base forms, the dosing vehicle was 0.5%methylcellulose in dilute HCl. Each dosing formulation was prepared byweighing the test article into the formulation container, followed byaddition of the appropriate volume of vehicle based on the weighedamount. If the test article appeared undissolved, the dosing formulationwas sonicated to aid dissolution. The dosing formulations were mixedwell and continuously stirred until filling the dosing syringes.Following dosing, any remaining formulation was stored at approximately−20° C.

Each animal was administered a single oral gavage (PO) dose. Anyobviously mis-dosed animals were replaced. The volume of dosingformulation that was administered to each animal was calculated based onthe pre-dose body weight obtained on the day of dosing.

Samples were collected at 15 min., 30 min., 1 h, 2 h, 3 h, 4, h, and 6 hpost-dose. K₂EDTA was used as an anticoagulant. At each non-terminalsample time, a 0.5 mL blood sample was collected from the JVC. Aftereach non-terminal sample removal, 0.4 mL strain-matched donor blood wastransfused via the JVC to replace removed blood, followed by a flush ofthe cannula with heparinized saline. If the cannula failed, retroorbitalor tail bleeding was used. The terminal sample was collected by cardiacpuncture and was approximately 0.5 mL volume.

Blood collection tubes were placed on ice immediately and centrifugedwithin 30 minutes at 4° C. to separate plasma. Samples were centrifugedat approximately 6000 rpm for 3 minutes at 4° C. Plasma was removed,placed into labeled polypropylene tubes, and quick frozen over dry ice.The plasma tubes were labeled with the study number, animal number, andsample time. Plasma specimens were stored at −70° C. until analysis.

Plasma samples were analyzed for oxymorphone/oxycodone concentrationsusing LC-MS/MS methods using the following steps: (1) Quantitation byLC-MS/MS with internal standard; (2) Determine anticipated calibrationcurve range; (3) Prepare calibration curve before and after sampleanalysis (N=2) in blank plasma using the following standards: (a)Minimum of 6 standard concentration; and (b) Acceptance criteria: Fivestandard concentrations minimum within the curve, must contain at leastone standard at both bottom and top of the range back calculated to ±20%of their nominal concentrations. It is acceptable to remove the upper orlower standards to bring the curve into ±20% nominal. Each batch alsocontained at least double blank, single blank, and carryover blankcontrols.

Example 1

Three Sprague Dawley rats were administered a dose of 1.77 mg/kgOxymorphone HCl Oral. The plasma concentrations of oxymorphone in eachrat, the mean plasma concentration of oxymorphone, and the standarddeviation at the seven time points are summarized in Table 2:

TABLE 2 Group 1: 1.77 mg/kg Oxymorphone HCl Oral Plasma oxymorphoneng/mL Time (h) Rat 1 Rat 2 Rat 3 Mean SD 0.25 0.379 0.862 1.144 0.7950.387 0.5 0.343 0.925 0.799 0.689 0.306 1 0.545 1.557 1.110 1.071 0.5072 0.728 1.826 0.621 1.058 0.667 3 0.457 0.676 BQL 0.378 0.345 4 0.5080.429 BQL 0.312 0.273 6 BQL 1.800 BQL 0.600 1.039 C_(max) (ng/mL) 0.7281.826 1.144 1.233 0.554 T_(max) (h ) 2.00 2.00 0.25 1.417 1.010AUC_(last) (h*ng/mL) BQL: <0.200 ng/mL

Example 2

Three Sprague Dawley rats were administered a dose of 3.54 mg/kgOxymorphone HCl Oral. The plasma concentrations of oxymorphone in eachrat, the mean plasma concentration of oxymorphone, and the standarddeviation at the seven time points are summarized in Table 3:

TABLE 3 Group 2: 3.54 mg/kg Oxymorphone HCl Oral Plasma oxymorphone(ng/mL) Time (h) Rat 4 Rat 5 Rat 6 Mean SD 0.25 4.958 3.246 1.767 3.3241.597 0.5 4.716 2.469 2.095 3.093 1.418 1 3.423 2.146 0.913 2.161 1.2552 1.273 2.434 1.639 1.782 0.594 3 0.577 1.635 1.276 1.163 0.538 4 0.3350.545 0.618 0.499 0.147 6 0.453 0.796 0.774 0.674 0.192 C_(max) (ng/mL)T_(max) (h) AUC_(last) (h*ng/mL) BQL: <0.200 ng/mL

Example 3

Three Sprague Dawley rats were administered a dose of 7.12 mg/kgOxymorphone Oleate (Ex No. B3) Oral. The plasma concentrations ofoxymorphone in each rat, the mean plasma concentration of oxymorphone,and the standard deviation at the seven time points are summarized inTable 4:

TABLE 4 Group 3: 7.12 mg/kg Oxymorphone Oleate Oral Plasma oxymorphone(ng/mL) Time (h) Rat 7 Rat 8 Rat 9 Mean SD 0.25 1.718 0.256 BQL 0.987 ND0.5 BQL 0.203 BQL 0.068 ND 1 0.242 0.245 0.448 0.312 0.118 2 BQL BQL0.239 0.080 ND 3 0.424 0.662 0.462 0.516 0.128 4 0.290 0.643 0.514 0.4820.179 6 1.828 0.614 1.167 1.203 0.608 C_(max) (ng/mL) T_(max) (h)AUC_(last) (h*ng/mL) BQL: <0.200 ng/mL ND: Not determined (N < 3)

Example 4

Three Sprague Dawley rats were administered a dose of 5.56 mg/kgOxymorphone Malate (Ex No. B5) Oral. The plasma concentrations ofoxymorphone in each rat, the mean plasma concentration of oxymorphone,and the standard deviation at the seven time points are summarized inTable 5:

TABLE 5 Group 4: 5.56 mg/kg Oxymorphone Malate Oral Plasma oxymorphone(ng/mL) Time (h) Rat 10 Rat 11 Rat 12 Mean SD 0.25 3.309 1.469 2.2892.356 0.922 0.5 6.131 2.268 2.821 3.740 2.089 1 7.497 3.572 4.122 5.0642.125 2 5.038 2.696 2.605 3.446 1.379 3 4.153 2.808 2.173 3.045 1.011 42.480 1.884 2.094 2.153 0.302 6 0.861 1.553 0.926 1.113 0.382 C_(max)(ng/mL) T_(max) (h) AUC_(last) (h*ng/mL) BQL: <0.200 ng/mL

Example 5

Three Sprague Dawley rats were administered a dose of 6.72 mg/kgOxymorphone Mandelate (Ex No. B1a) Oral. The plasma concentrations ofoxymorphone in each rat, the mean plasma concentration of oxymorphone,and the standard deviation at the seven time points are summarized inTable 6:

TABLE 6 Group 5: 6.72 mg/kg Oxymorphone Mandelate Oral (not completelysoluble) Plasma oxymorphone (ng/mL) Time (h) Rat 13 Rat 14 Rat 15 MeanSD 0.25 0.649 0.889 0.824 0.787 0.124 0.5 0.660 1.017 0.705 0.794 0.1941 0.500 1.434 0.612 0.849 0.510 2 0.543 1.445 0.691 0.893 0.484 3 0.5460.870 0.718 0.711 0.162 4 0.667 0.799 0.477 0.648 0.162 6 0.354 1.4820.836 0.891 0.566 C_(max) (ng/mL) T_(max) (h) AUC_(last) (h*ng/mL) BQL:<0.200 ng/mL

Example 6

Three Sprague Dawley rats were administered a dose of 5.48 mg/kgOxymorphone Mandelate (Ex No. B1b) Oral. The plasma concentrations ofoxymorphone in each rat, the mean plasma concentration of oxymorphone,and the standard deviation at the seven time points are summarized inTable 7:

TABLE 7 Group 6: 5.48 mg/kg Oxymorphone Mandelate Oral Plasmaoxymorphone (ng/mL) Time (h) Rat 16 Rat 17 Rat 18 Mean SD 0.25 0.9762.781 3.377 2.378 1.250 0.5 1.162 2.229 3.898 2.430 1.379 1 1.320 2.3854.951 2.885 1.866 2 1.273 1.607 2.615 1.832 0.699 3 0.884 0.821 0.6230.776 0.136 4 0.465 0.471 0.223 0.386 0.141 6 0.594 0.321 2.896 1.2701.414 C_(max) (ng/mL) T_(max) (h) AUC_(last) (h*ng/mL) BQL: <0.200 ng/mL

Example 7

Three Sprague Dawley rats were administered a dose of 6.01 mg/kgOxymorphone Lactate (Ex No. B2a) Oral. The plasma concentrations ofoxymorphone in each rat, the mean plasma concentration of oxymorphone,and the standard deviation at the seven time points are summarized inTable 8:

TABLE 8 Group 7: 6.01 mg/kg Oxymorphone Lactate Oral Plasma oxymorphone(ng/mL) Time (h) Rat 19 Rat 20 Rat 21 Mean SD 0.25 3.689 1.782 1.8362.436 1.086 0.5 4.377 2.711 1.514 2.867 1.438 1 2.485 2.347 1.989 2.2740.256 2 1.351 2.022 0.995 1.456 0.521 3 0.501 1.422 0.408 0.777 0.561 40.218 0.998 0.451 0.556 0.400 6 1.128 1.784 0.466 1.126 0.659 C_(max)(ng/mL) T_(max) (h) AUC_(last) (h*ng/mL) BQL: <0.200 ng/mL

Example 8

Three Sprague Dawley rats were administered a dose of 4.93 mg/kgOxymorphone Lactate (Ex No. B2a) Oral. The plasma concentrations ofoxymorphone in each rat, the mean plasma concentration of oxymorphone,and the standard deviation at the seven time points are summarized inTable 9:

TABLE 9 Group 8: 4.93 mg/kg Oxymorphone Lactate Oral Plasma oxymorphone(ng/mL) Time (h) Rat 22 Rat 23 Rat 24 Mean SD 0.25 4.760 0.740 3.4882.996 2.055 0.5 3.470 2.347 2.514 2.777 0.606 1 3.749 2.839 1.846 2.8110.952 2 1.698 2,279 2.062 2.013 0.294 3 1.325 1.306 1.199 1.277 0.068 41.504 0.728 0.642 0.958 0.475 6 1.323 0.915 1.915 1.384 0.503 C_(max)(ng/mL) T_(max) (h) AUC_(last) (h*ng/mL) BQL: <0.200 ng/mL

Example 9

Three Sprague Dawley rats were administered a dose of 7.4 mg/kgOxymorphone Stearate (Ex No. B4) Oral. The plasma concentrations ofoxymorphone in each rat, the mean plasma concentration of oxymorphone,and the standard deviation at the seven time points are summarized inTable 10:

TABLE 10 Group 9: 7.4 mg/kg Oxymorphone Stearate Oral (not completelysoluble) Plasma oxymorphone (ng/mL) Time (h) Rat 25 Rat 26 Rat 27 MeanSD 0.25 0.372 1.047 2.369 1.263 1.016 0.5 0.938 1.560 3.332 1.943 1.2421 0.640 1.484 3.230 1.785 1.321 2 0.745 1.031 2.208 1.328 0.775 3 0.7320.763 1.927 1.141 0.681 4 0.680 0.986 0.845 0.837 0.153 6 6.220 3.1761.077 3.491 2.586 C_(max) (hg/mL) T_(max) (h) AUC_(last) (h*ng/mL) BQL:<0.200 ng/mL

Example 10

Three Sprague Dawley rats were administered a dose of 6.16 mg/kgOxymorphone Alanine (Ex No. B6) Oral. The plasma concentrations ofoxymorphone in each rat, the mean plasma concentration of oxymorphone,and the standard deviation at the seven time points are summarized inTable 11:

TABLE 11 Group 10: 6.16 mg/kg Oxymorphone Alanine Oral Plasmaoxymorphone (ng/mL) Time (h) Rat 28 Rat 29 Rat 30 Mean SD 0.25 4.5941.841 2.008 2.814 1.543 0.5 3.106 6.227 3.877 4.403 1.626 1 2.794 2.9013.409 3.035 0.329 2 1.863 3.212 1.688 2.254 0.834 3 0.997 1.247 0.6830.976 0.283 4 0.642 0.600 0.772 0.671 0.090 6 0.394 1.042 0.259 0.5650.419 C_(max) (ng/mL) T_(max) (h) AUC_(last) (h*ng/ml) BQL: <0.200 ng/mL

Example 11

Three Sprague Dawley rats were administered a dose of 5.41 mg/kgOxymorphone Alanine (Ex No. B6) Oral. The plasma concentrations ofoxymorphone in each rat, the mean plasma concentration of oxymorphone,and the standard deviation at the seven time points are summarized inTable 12:

TABLE 12 Group 11: 5.41 mg/kg Oxymorphone Alanine Oral Plasmaoxymorphone (ng/mL) Time (h) Rat 31 Rat 32 Rat 33 Mean SD 0.25 7.1623.700 8.770 6.544 2.591 0.5 5.382 2.835 5.058 4.425 1.386 1 5.630 2.8468.661 5.712 2.908 2 2.536 3.074 5.179 3.596 1.397 3 1.497 No Sample2.029 1.763 ND 4 0.348 1.496 0.722 0.855 0.585 6 0.516 0.442 BQL 0.3190.279 C_(max) (ng/mL) T_(max) (h) AUC_(last) (h*ng/mL) BQL: <0.200 ng/mL

Example 12

Three Sprague Dawley rats were administered a dose of 6.01 mg/kgOxymorphone Mandelate (Ex No. B8) Oral. The plasma concentrations ofoxymorphone in each rat, the mean plasma concentration of oxymorphone,and the standard deviation at the seven time points are summarized inTable 13:

TABLE 13 Group 12: 6.01 mg/kg Oxymorphone Mandelate Oral Plasmaoxymorphone (ng/mL) Time (h) Rat 34 Rat 35 Rat 36 Mean SD 0.25 5.2941.391 1.909 2.865 2.120 0.5 2.736 1.530 1.429 1.898 0.727 1 3.083 2.1042.436 2.541 0.498 2 1.423 1.562 1.786 1.590 0.183 3 0.351 1.146 1.0500.849 0.434 4 0.383 0.969 0.436 0.596 0.324 6 0.355 1.426 0.421 0.7340.600 C_(max) (ng/mL) T_(max) (h) AUC_(last) (h*ng/mL) BQL: <0.200 ng/mL

Example 13

Three Sprague Dawley rats were administered a dose of 6.02 mg/kgOxymorphone Malate (Ex No. B9) Oral. The plasma concentrations ofoxymorphone in each rat, the mean plasma concentration of oxymorphone,and the standard deviation at the seven time points are summarized inTable 14:

TABLE 14 Group 13: 6.02 mg/kg Oxymorphone Malate Oral Plasma oxymorphone(ng/mL) Time (h) Rat 37 Rat 38 Rat 39 Mean SD 0.25 4.115 4.829 6.0965.013 1.003 0.5 2.805 4.386 2.200 3.130 1.129 1 2.379 3.955 2.999 3.1110.794 2 3.028 1.615 2.540 2.394 0.718 3 1.059 1.410 1.128 1.199 0.186 40.456 0.856 0.755 0.689 0.208 6 0.490 0.310 2.493 1.098 1.212 C_(max)(ng/mL) T_(max) (h) AUC_(last) (h*ng/mL) BQL: <0.200 ng/mL

Example 14

Three Sprague Dawley rats per group were administered a 0.89 mg/kg doseof an oxycodone compound. The plasma concentrations of oxycodone in eachrat, the mean plasma concentration of oxymorphone, and the standarddeviation at the seven time points are summarized in Table 15:

TABLE 15 Test Dose^(a) Time Plasma Concentration (ng/mL) by SubjectGroup Article (mg/kg) (h) 1M001 1M002 1M003 Mean SD N 1 Oxycodone 0.890.25 2.39 1.19 1.26 1.61 0.67 3 HCl Oral 0.5 1.97 0.682 1.04 1.23 0.66 31 1.40 BLQ 0.678 1.04 0.51 2 2 BLQ BLQ BLQ BLQ — 0 3 BLQ BLQ BLQ BLQ — 04 BLQ BLQ BLQ BLQ — 0 6 BLQ BLQ BLQ BLQ — 0 Test Dose Time PlasmaConcentration (ng/mL) by Subject Group Article (mg/kg) (h) 2M001 2M0022M003 Mean SD N 2 Oxycodone 0.89 0.25 3.07 1.53 3.31 2.64 0.97 3Mandelate 0.5 3.29 1.73 2.98 2.67 0.83 3 Oral 1 1.48 BLQ 2.37 1.93 0.632 2 0.908 BLQ 0.596 0.752 0.221 2 3 0.671 BLQ BLQ 0.671 n = 1 1 4 BLQBLQ BLQ BLQ — 0 6 BLQ BLQ BLQ BLQ — 0 Test Dose Time PlasmaConcentration (ng/mL) by Subject Group Article (mg/kg) (h) 3M001 3M0023M003 Mean SD N 3 Oxycodone 0.89 0.25 0.742 1.14 1.09 0.991 0.217 3Malate 0.5 0.696 1.06 1.36 1.04 0.33 3 Oral 1 0.767 1.14 1.62 1.18 0.433 2 0.955 0.782 1.22 0.986 0.221 3 3 BLQ BLQ 0.792 0.792 n = 1 1 4 BLQBLQ 0.788 0.788 n = 1 1 6 BLQ BLQ BLQ BLQ — 0 Test Dose Time PlasmaConcentration (ng/mL) by Subject Group Article (mg/kg) (h) 4M001 4M0024M003 Mean SD N 4 Oxycodone 0.89 0.25 BLQ BLQ BLQ BLQ — 0 Dimalate 0.5BLQ BLQ BLQ BLQ — 0 Oral 1 0.933 BLQ BLQ 0.933 n = 1 1 2 BLQ BLQ BLQ BLQ— 0 3 BLQ BLQ BLQ BLQ — 0 4 BLQ BLQ BLQ BLQ — 0 6 BLQ BLQ BLQ BLQ — 0Test Dose Time Plasma Concentration (ng/mL) by Subject Group Article(mg/kg) (h) 5M001 5M002 5M003 Mean SD N 5 Oxycodone 0.89 0.25 5.59 7.273.09 5.32 2.10 3 Lactate 0.5 5.19 8.71 4.32 6.07 2.32 3 Oral 1 3.61 6.312.12 4.01 2.12 3 2 0.790 2.11 BLQ 1.45 0.93 2 3 BLQ 1.24 BLQ 1.24 n = 11 4 BLQ 1.69 BLQ 1.69 n = 1 1 6 BLQ BLQ BLQ BLQ — 0 Test Dose TimePlasma Concentration (ng/mL) by Subject Group Article (mg/kg) (h) 6M0016M002 6M003 Mean SD N 6 Oxycodone 0.89 0.25 BLQ 4.92 1.90 3.41 2.14 2Stearate 0.5 2.83 7.57 4.73 5.04 2.39 3 Oral 1 1.92 4.86 4.74 3.84 1.663 2 1.41 2.13 1.93 1.82 0.37 3 3 1.14 1.31 1.75 1.40 0.31 3 4 1.02 1.441.39 1.28 0.23 3 6 0.914 BLQ 1.48 1.20 0.40 2 Test Dose Time PlasmaConcentration (ng/mL) by Subject Group Article (mg/kg) (h) 7M001 7M0027M003 Mean SD N 7 Oxycodone 0.89 0.25 0.912 3.12 BLQ 2.02 1.56 2Palmitate 0.5 2.79 6.17 1.87 3.61 2.26 3 Oral 1 3.45 4.49 1.65 3.20 1.443 2 1.84 2.02 1.17 1.68 0.45 3 3 2.11 1.51 BLQ 1.81 0.42 2 4 1.93 1.75BLQ 1.84 0.13 2 6 1.44 BLQ BLQ 1.44 n = 1 1 Test Dose Time PlasmaConcentration (ng/mL) by Subject Group Article (mg/kg) (h) 8M001 8M0028M003 Mean SD N 8 Oxycodone 0.89 0.25 2.34 BLQ 2.31 2.33 0.02 2 Oleate0.5 3.40 1.82 3.02 2.75 0.82 3 Oral 1 2.35 2.03 2.20 2.19 0.16 3 2 1.031.21 1.34 1.19 0.16 3 3 BLQ BLQ 1.01 1.01 n = 1 1 4 BLQ BLQ BLQ BLQ — 06 BLQ BLQ 0.900 0.900 n = 1 1

These and other modifications and variations to the invention may bepracticed by those of ordinary skill in the art without departing fromthe spirit and scope of the invention, which is more particularly setforth in the appended claims. In addition, it should be understood thataspects of the various embodiments may be interchanged in whole or inpart. Furthermore, those of ordinary skill in the art will appreciatethat the foregoing description is by way of example only, and it is notintended to limit the invention as further described in such appendedclaims. Therefore, the spirit and scope of the appended claims shouldnot be limited to the exemplary description of the versions containedherein.

What is claimed is:
 1. An abuse-resistant opioid compound represented byFormula I:O—X_(n)  (I) wherein, O is an opioid selected from the group consistingof oxycodone and oxymorphone; each X is an independent chemical moietythat is safe for human consumption and is selected from the groupconsisting of an amino acid, a dipeptide, an α-hydroxy acid, adicarboxylic acid, and a fatty acid; and n is from 1 to
 10. 2. Theabuse-resistant opioid compound of claim 1, wherein X comprises alanine,proline, carnosine, lactic acid, mandelic acid, malic acid, tartaricacid, succinic acid, citric acid, sorbic acid, oleic acid, or stearicacid.
 3. The abuse-resistant opioid compound of claim 1, wherein theabuse-resistant opioid compound is represented by Formula IV:

wherein, R¹ is selected from the group consisting of hydroxy, alkoxy,and —OC(O)-alkoxy; R² is selected from the group consisting of hydroxyand —OC(O)R⁴; R³ and R⁴ are selected from the group consisting of—CHR⁵R⁶, —C_(a)H_(b), —C₂H₃R⁷R⁸, —C₂H₄NHC(O)C₂H₃R⁹R¹⁰,—C₂H₄NC(O)C₂H₃R¹¹R¹², —C₂H₄NC(O)CHR²³R²⁴, —C₂H₃CHR²⁹R³⁰,—C₂H₄NHC(O)(CH)₂C(O)OH, —C₂H₄C(O)OCHR³¹R³², —C₂H₄NHC(O)CHR³³R³⁴, and—C₃H₅R³⁵R³⁶; R⁵ is selected from the group consisting of hydroxy,—OC(O)-alkoxy; —NHC(O)CHR¹⁷R¹⁸, —NHC(O)C₂H₃R¹⁹R²⁰, —OC(O)CHR²¹R²²,4-methylimidazole, —OC(O)C₂H₄NH₂, —OC(O)C₂H₄NHC(O)CHR²⁵R²⁶,—OC(O)C₂H₃R²⁷R²⁸, —OC(O)(CH₂)₁₆CH₃, —OC(O)C₂H₄C(O)OH,—OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, —CH₂COOH, —OC(O)CH₃, —CHR³⁷R³⁸,—CH₂C(O)OCHR³⁹R⁴⁰, —OC(O)C₃H₅R⁴¹R⁴², —CH₂C(O)OC₂H₅,—OC(O)C₂H₄NHC(O)C₄H₇NH, —OC(O)C₄H₇NH, —OC(O)C₂H₃NHC(O)C₂H₃R⁴³R⁴⁴,—OC(O)C₂H₄CHR⁴⁵R⁴⁶, and —OC(O)C₂H₄NHC(O)C₃H₅R⁴⁷R⁴⁸; R⁶ is selected fromthe group consisting of alkyl, hydroxy, aryl, —CH₂COOH, —NHC(O)C₂H₄NH₂,—C(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, —C(O)(CH₂)₁₆CH₃, —CH₂C(O)CHR⁴⁹R⁵⁰,—CH₂C(O)OC₄H₉, —OC(O)CH₃, —OC(O)C₂H₄C(O)OH, —NHC(O)C₂H₄NHC(O)CHR⁵¹R⁵²,and —OC(O)(CH₂)₁₆CH₃; R⁷ is selected from the group consisting ofhydroxy, amino, —OC(O)CH₃, —NHC(O)CHR⁵³R⁵⁴, —OC(O)CHR⁵⁵R⁵⁶, and—OC(O)C₂H₃R⁵⁷R⁵⁸; R⁸ is selected from the group consisting of carboxyl,hydroxy, —C(O)OC₄H₉, —OC(O)CH₃, and —C(O)OCHR⁵⁹R⁶⁰; R⁹ is selected fromthe group consisting of hydroxy, carboxyl, —NHC(O)CHR⁶¹R⁶², and—C(O)OCHR⁶³R⁶⁴; R¹⁰, R¹², R²⁹, R³¹, R³⁵, R³⁹, R⁴², R⁴⁴, R⁴⁶, R⁴⁸, R⁵⁷,R⁵⁹, R⁶³, R⁶⁹, R⁷³, R⁷⁵ are each independently carboxyl; R¹¹, R⁴³, R⁵²,R⁵³, R⁵⁶, R⁵⁸, R⁷⁰, R⁷⁷, R⁷⁹, R⁸⁴ are each independently hydroxy; R¹⁷,R²⁴, R³⁴ are each independently selected from the group consisting ofhydroxy, aryl, and alkyl; R¹⁸ is selected from the group consisting of—CH₂COOH and hydroxy; R¹⁹ and R²⁰ are each independently selected fromthe group consisting of hydroxy and carboxyl; R²¹ is selected from thegroup consisting of alkyl, aryl, substituted aryl, hydroxy, amino,—OC(O)CH₃, —NHC(O)CHR⁶⁷R⁶⁸, —NHC(O)C₂H₃CHR⁶⁹R⁷⁰, and —NHC(O)C₄H₇NH; R²²is selected from the group consisting of alkyl, hydroxy, amino,—NHC(O)CHR⁷¹R⁷², —CH₂COOH, —OC(O)(CH₂)₁₆CH₃, —OC(O)CH₃, —CH₂COOH,—(CH₂)₂COOH, —CH₂C(O)OC₄H₉, —CHR⁷³R⁷⁴, —NHC(O)C₄H₇NH,—OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, and —CHR⁷⁵R⁷⁶; R²³ is selected from thegroup consisting of hydroxy, aryl, —CH₂COOH, and—OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃; R²⁵ is selected from the group consisting ofalkyl, —C₂H₄C(O)OH, substituted aryl, and amino; R²⁶ is selected fromthe group consisting of alkyl, hydroxy, amino, substituted aryl,—NHC(O)CH₃, and —(CH₂)₂COOH; R²⁷ is selected from the group consistingof carboxyl, —NHC(O)CHR⁷⁷R⁷⁸, and —C(O)OC₄H₉; R²⁸ is selected from thegroup consisting of amino, hydroxy, carboxyl, and —OC(O)CH₃; R³⁰ is—NHC(O)CHR⁷⁹R⁸⁰; R³² is selected from the group consisting of aryl,—CH₂COOH, and alkyl; R³³ is selected from the group consisting of—CH₂COOH and hydroxy; R³⁶ is NHC(O)CHR⁸³R⁸⁴; R³⁷, R⁶¹, R⁷⁴ are eachindependently selected from the group consisting of hydroxy and—OC(O)CH₃; R³⁸ is selected from the group consisting of carboxyl and—C(O)OCHR⁸¹R⁸²; R⁴¹, R⁴⁵, and R⁴⁷ are each independently amino; R⁴⁰,R⁶², R⁶⁴ are each independently selected from the group consisting ofalkyl and aryl; R⁴⁹ and R⁷⁶ are each independently —OC(O)CH₃; R⁵⁰, R⁵¹,R⁵⁴, R⁵⁵, R⁶⁰, R⁷⁸, R⁸⁰, R⁸³ are each independently alkyl; R⁶⁷ isselected from the group consisting of alkyl and —NHC(O)CH₃; R⁶⁸ isselected from the group consisting of hydroxy and —(CH₂)₄NH₂; R⁷¹ isselected from the group consisting of hydroxy, —NHC(O)CH₃, and amino;R⁷² is selected from the group consisting of alkyl and —C₄H₈NH₂; R⁸¹ isselected from the group consisting of carboxyl, aryl, and —CH₂COOH; R⁸²is selected from the group consisting of alkyl, aryl, carboxyl, and—CH₂COOH; T is a pharmaceutically acceptable salt; a is from 1 to 30; bis from 1 to 50; c is from 0 to 5; and d is from 1 to
 10. 4. Theabuse-resistant opioid compound of claim 3, wherein the abuse-resistantcompound is selected from the group consisting of:


5. A drug delivery system, comprising an abuse-resistant opioid compoundrepresented by Formula I:O—X_(n)  (I) wherein, O is an opioid selected from the group consistingof oxycodone and oxymorphone; each X is an independent chemical moietythat is safe for human consumption and is selected from the groupconsisting of an amino acid, a dipeptide, an a-hydroxy acid, adicarboxylic acid, and a fatty acid; and n is from 1 to
 10. 6. The drugdelivery system of claim 5, wherein X comprises alanine, proline,carnosine, lactic acid, mandelic acid, malic acid, tartaric acid,succinic acid, citric acid, sorbic acid, oleic acid, or stearic acid. 7.The drug delivery system of claim 5, wherein the abuse-resistant opioidcompound is represented by Formula IV:

wherein, R¹ is selected from the group consisting of hydroxy, alkoxy,and —OC(O)-alkoxy; R² is selected from the group consisting of hydroxyand —OC(O)R⁴; R³ and R⁴ are selected from the group consisting of—CHR⁵R⁶, —C_(a)H_(b), —C₂H₃R⁷R⁸, —C₂H₄NHC(O)C₂H₃R⁹R¹⁰,—C₂H₄NC(O)C₂H₃R¹¹R¹², —C₂H₄NC(O)CHR²³R²⁴, —C₂H₃CHR²⁹R³⁰,—C₂H₄NHC(O)(CH)₂C(O)OH, —C₂H₄C(O)OCHR³¹R³², —C₂H₄NHC(O)CHR³³R³⁴, and—C₃H₅R³⁵R³⁶; R⁵ is selected from the group consisting of hydroxy,—OC(O)-alkoxy; —NHC(O)CHR¹⁷R¹⁸, —NHC(O)C₂H₃R¹⁹R²⁰, —OC(O)CHR²¹R²²,4-methylimidazole, —OC(O)C₂H₄NH₂, —OC(O)C₂H₄NHC(O)CHR²⁵R²⁶,—OC(O)C₂H₃R²⁷R²⁸, —OC(O)(CH₂)₁₆CH₃, —OC(O)C₂H₄C(O)OH,—OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, —CH₂COOH, —OC(O)CH₃, —CHR³⁷R³⁸,—CH₂C(O)OCHR³⁹R⁴⁰, —OC(O)C₃H₅R⁴¹R⁴², —CH₂C(O)OC₂H₅,—OC(O)C₂H₄NHC(O)C₄H₇NH, —OC(O)C₄H₇NH, —OC(O)C₂H₃NHC(O)C₂H₃R⁴³R⁴⁴,—OC(O)C₂H₄CHR⁴⁵R⁴⁶, and —OC(O)C₂H₄NHC(O)C₃H₅R⁴⁷R⁴⁸; R⁶ is selected fromthe group consisting of alkyl, hydroxy, aryl, —CH₂COOH, —NHC(O)C₂H₄NH₂,—C(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, —C(O)(CH₂)₁₆CH₃, —CH₂C(O)CHR⁴⁹R⁵⁰,—CH₂C(O)OC₄H₉, —OC(O)CH₃, —OC(O)C₂H₄C(O)OH, —NHC(O)C₂H₄NHC(O)CHR⁵¹R⁵²,and —OC(O)(CH₂)₁₆CH₃; R⁷ is selected from the group consisting ofhydroxy, amino, —OC(O)CH₃, —NHC(O)CHR⁵³R⁵⁴, —OC(O)CHR⁵⁵R⁵⁶, and—OC(O)C₂H₃R⁵⁷R⁵⁸; R⁸ is selected from the group consisting of carboxyl,hydroxy, —C(O)OC₄H₉, —OC(O)CH₃, and —C(O)OCHR⁵⁹R⁶⁰; R⁹ is selected fromthe group consisting of hydroxy, carboxyl, —NHC(O)CHR⁶¹R⁶², and—C(O)OCHR⁶³R⁶⁴; R¹⁰, R¹², R²⁹, R³¹, R³⁵, R³⁹, R⁴², R⁴⁴, R⁴⁶, R⁴⁸, R⁵⁷,R⁵⁹, R⁶³, R⁶⁹, R⁷³, R⁷⁵ are each independently carboxyl; R¹¹, R⁴³, R⁵²,R⁵³, R⁵⁶, R⁵⁸, R⁷⁰, R⁷⁷, R⁷⁹, R⁸⁴ are each independently hydroxy; R¹⁷,R²⁴, R³⁴ are each independently selected from the group consisting ofhydroxy, aryl, and alkyl; R¹⁸ is selected from the group consisting of—CH₂COOH and hydroxy; R¹⁹ and R²⁰ are each independently selected fromthe group consisting of hydroxy and carboxyl; R²¹ is selected from thegroup consisting of alkyl, aryl, substituted aryl, hydroxy, amino,—OC(O)CH₃, —NHC(O)CHR⁶⁷R⁶⁸, —NHC(O)C₂H₃CHR⁶⁹R⁷⁰, and —NHC(O)C₄H₇NH; R²²is selected from the group consisting of alkyl, hydroxy, amino,—NHC(O)CHR⁷¹R⁷², —CH₂COOH, —OC(O)(CH₂)₁₆CH₃, —OC(O)CH₃, —CH₂COOH,—(CH₂)₂COOH, —CH₂C(O)OC₄H₉, —CHR⁷³R⁷⁴, —NHC(O)C₄H₇NH,—OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, and —CHR⁷⁵R⁷⁶; R²³ is selected from thegroup consisting of hydroxy, aryl, —CH₂COOH, and—OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃; R²⁵ is selected from the group consisting ofalkyl, —C₂H₄C(O)OH, substituted aryl, and amino; R²⁶ is selected fromthe group consisting of alkyl, hydroxy, amino, substituted aryl,—NHC(O)CH₃, and —(CH₂)₂COOH; R²⁷ is selected from the group consistingof carboxyl, —NHC(O)CHR⁷⁷R⁷⁸, and —C(O)OC₄H₉; R²⁸ is selected from thegroup consisting of amino, hydroxy, carboxyl, and —OC(O)CH₃; R³⁰ is—NHC(O)CHR⁷⁹R⁸⁰; R³² is selected from the group consisting of aryl,—CH₂COOH, and alkyl; R³³ is selected from the group consisting of—CH₂COOH and hydroxy; R³⁶ is NHC(O)CHR⁸³R⁸⁴; R³⁷, R⁶¹, R⁷⁴ are eachindependently selected from the group consisting of hydroxy and—OC(O)CH₃; R³⁸ is selected from the group consisting of carboxyl and—C(O)OCHR⁸¹R⁸²; R⁴¹, R⁴⁵, and R⁴⁷ are each independently amino; R⁴⁰,R⁶², R⁶⁴ are each independently selected from the group consisting ofalkyl and aryl; R⁴⁹ and R⁷⁶ are each independently —OC(O)CH₃; R⁵⁰, R⁵¹,R⁵⁴, R⁵⁵, R⁶⁰, R⁷⁸, R⁸⁰, R⁸³ are each independently alkyl; R⁶⁷ isselected from the group consisting of alkyl and —NHC(O)CH₃; R⁶⁸ isselected from the group consisting of hydroxy and —(CH₂)₄NH₂; R⁷¹ isselected from the group consisting of hydroxy, —NHC(O)CH₃, and amino;R⁷² is selected from the group consisting of alkyl and —C₄H₈NH₂; R⁸¹ isselected from the group consisting of carboxyl, aryl, and —CH₂COOH; R⁸²is selected from the group consisting of alkyl, aryl, carboxyl, and—CH₂COOH; T is a pharmaceutically acceptable salt; a is from 1 to 30; bis from 1 to 50; c is from 0 to 5; and d is from 0 to
 10. 8. Apharmaceutical composition, comprising: an abuse-resistant opioidcompound; and at least one pharmaceutical additive, wherein theabuse-resistant opioid compound is represented by Formula I:O—X_(n)  (I) wherein, O is an opioid selected from the group consistingof oxycodone and oxymorphone; each X is an independent chemical moietythat is safe for human consumption and is selected from the groupconsisting of an amino acid, a dipeptide, an a-hydroxy acid, adicarboxylic acid, and a fatty acid; and n is from 1 to
 10. 9. Thepharmaceutical composition of claim 8, wherein X comprises alanine,proline, carnosine, lactic acid, mandelic acid, malic acid, tartaricacid, succinic acid, citric acid, sorbic acid, oleic acid, or stearicacid.
 10. The pharmaceutical composition of claim 8, wherein theabuse-resistant opioid compound is represented by Formula IV:

wherein, R¹ is selected from the group consisting of hydroxy, alkoxy,and —OC(O)-alkoxy; R² is selected from the group consisting of hydroxyand —OC(O)R⁴; R³ and R⁴ are selected from the group consisting of—CHR⁵R⁶, —C_(a)H_(b), —C₂H₃R⁷R⁸, —C₂H₄NHC(O)C₂H₃R⁹R¹⁰,—C₂H₄NC(O)C₂H₃R¹¹R¹², —C₂H₄NC(O)CHR²³R²⁴, —C₂H₃CHR²⁹R³⁰,—C₂H₄NHC(O)(CH)₂C(O)OH, —C₂H₄C(O)OCHR³¹R³², —C₂H₄NHC(O)CHR³³R³⁴, and—C₃H₅R³⁵R³⁶; R⁵ is selected from the group consisting of hydroxy,—OC(O)-alkoxy; —NHC(O)CHR¹⁷R¹⁸, —NHC(O)C₂H₃R¹⁹R²⁰, —OC(O)CHR²¹R²²,4-methylimidazole, —OC(O)C₂H₄NH₂, —OC(O)C₂H₄NHC(O)CHR²⁵R²⁶,—OC(O)C₂H₃R²⁷R²⁸, —OC(O)(CH₂)₁₆CH₃, —OC(O)C₂H₄C(O)OH,—OC(O)(CH₂)(CH)₂(CH₂)₇CH₃, —CH₂COOH, —OC(O)CH₃, —CHR³⁷R³⁸,—CH₂C(O)OCHR³⁹R⁴⁰, —OC(O)C₃H₅R⁴¹R⁴², —CH₂C(O)OC₂H₅,—OC(O)C₂H₄NHC(O)C₄H₇NH, —OC(O)C₄H₇NH, —OC(O)C₂H₃NHC(O)C₂H₃R⁴³R⁴⁴,—OC(O)C₂H₄CHR⁴⁵R⁴⁶, and —OC(O)C₂H₄NHC(O)C₃H₅R⁴⁷R⁴⁸; R⁶ is selected fromthe group consisting of alkyl, hydroxy, aryl, —CH₂COOH, —NHC(O)C₂H₄NH₂,—C(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, —C(O)(CH₂)₁₆CH₃, —CH₂C(O)CHR⁴⁹R⁵⁰,—CH₂C(O)OC₄H₉, —OC(O)CH₃, —OC(O)C₂H₄C(O)OH, —NHC(O)C₂H₄NHC(O)CHR⁵¹R⁵²,and —OC(O)(CH₂)₁₆CH₃; R⁷ is selected from the group consisting ofhydroxy, amino, —OC(O)CH₃, —NHC(O)CHR⁵³R⁵⁴, —OC(O)CHR⁵⁵R⁵⁶, and—OC(O)C₂H₃R⁵⁷R⁵⁸; R⁸ is selected from the group consisting of carboxyl,hydroxy, —C(O)OC₄H₉, —OC(O)CH₃, and —C(O)OCHR⁵⁹R⁶⁰; R⁹ is selected fromthe group consisting of hydroxy, carboxyl, —NHC(O)CHR⁶¹R⁶², and—C(O)OCHR⁶³R⁶⁴; R¹⁰, R¹², R²⁹, R³¹, R³⁵, R³⁹, R⁴², R⁴⁴, R⁴⁶, R⁴⁸, R⁵⁷,R⁵⁹, R⁶³, R⁶⁹, R⁷³, R⁷⁵ are each independently carboxyl; R¹¹, R⁴³, R⁵²,R⁵³, R⁵⁶, R⁵⁸, R⁷⁰, R⁷⁷, R⁷⁹, R⁸⁴ are each independently hydroxy; R¹⁷,R²⁴, R³⁴ are each independently selected from the group consisting ofhydroxy, aryl, and alkyl; R¹⁸ is selected from the group consisting of—CH₂COOH and hydroxy; R¹⁹ and R²⁰ are each independently selected fromthe group consisting of hydroxy and carboxyl; R²¹ is selected from thegroup consisting of alkyl, aryl, substituted aryl, hydroxy, amino,—OC(O)CH₃, —NHC(O)CHR⁶⁷R⁶⁸, —NHC(O)C₂H₃CHR⁶⁹R⁷⁰, and —NHC(O)C₄H₇NH; R²²is selected from the group consisting of alkyl, hydroxy, amino,—NHC(O)CHR⁷¹R⁷², —CH₂COOH, —OC(O)(CH₂)₁₆CH₃, —OC(O)CH₃, —CH₂COOH,—(CH₂)₂COOH, —CH₂C(O)OC₄H₉, —CHR⁷³R⁷⁴, —NHC(O)C₄H₇NH,—OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, and —CHR⁷⁵R⁷⁶; R²³ is selected from thegroup consisting of hydroxy, aryl, —CH₂COOH, and—OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃; R²⁵ is selected from the group consisting ofalkyl, —C₂H₄C(O)OH, substituted aryl, and amino; R²⁶ is selected fromthe group consisting of alkyl, hydroxy, amino, substituted aryl,—NHC(O)CH₃, and —(CH₂)₂COOH; R²⁷ is selected from the group consistingof carboxyl, —NHC(O)CHR⁷⁷R⁷⁸, and —C(O)OC₄H₉; R²⁸ is selected from thegroup consisting of amino, hydroxy, carboxyl, and —OC(O)CH₃; R³⁰ is—NHC(O)CHR⁷⁹R⁸⁰; R³² is selected from the group consisting of aryl,—CH₂COOH, and alkyl; R³³ is selected from the group consisting of—CH₂COOH and hydroxy; R³⁶ is NHC(O)CHR⁸³R⁸⁴; R³⁷, R⁶¹, R⁷⁴ are eachindependently selected from the group consisting of hydroxy and—OC(O)CH₃; R³⁸ is selected from the group consisting of carboxyl and—C(O)OCHR⁸¹R⁸²; R⁴¹, R⁴⁵, and R⁴⁷ are each independently amino; R⁴⁰,R⁶², R⁶⁴ are each independently selected from the group consisting ofalkyl and aryl; R⁴⁹ and R⁷⁶ are each independently —OC(O)CH₃; R⁵⁰, R⁵¹,R⁵⁴, R⁵⁵, R⁶⁰, R⁷⁸, R⁸⁰, R⁸³ are each independently alkyl; R⁶⁷ isselected from the group consisting of alkyl and —NHC(O)CH₃; R⁶⁸ isselected from the group consisting of hydroxy and —(CH₂)₄NH₂; R⁷¹ isselected from the group consisting of hydroxy, —NHC(O)CH₃, and amino;R⁷² is selected from the group consisting of alkyl and —C₄H₈NH₂; R⁸¹ isselected from the group consisting of carboxyl, aryl, and —CH₂COOH; R⁸²is selected from the group consisting of alkyl, aryl, carboxyl, and—CH₂COOH; T is a pharmaceutically acceptable salt; a is from 1 to 30; bis from 1 to 50; c is from 0 to 5; and d is from 0 to
 10. 11. A methodof delivering an active ingredient to a subject, comprisingadministering a therapeutically effective amount of an abuse-resistantopioid compound to a subject in need thereof, wherein theabuse-resistant opioid compound is represented by Formula I:O—X_(n)  (I) wherein, O is an opioid selected from the group consistingof oxycodone and oxymorphone; each X is an independent chemical moietythat is safe for human consumption and is selected from the groupconsisting of an amino acid, a dipeptide, an a-hydroxy acid, adicarboxylic acid, and a fatty acid; and n is from 1 to
 10. 12. Themethod of claim 11, wherein X comprises alanine, proline, carnosine,lactic acid, mandelic acid, malic acid, tartaric acid, succinic acid,citric acid, sorbic acid, oleic acid, or stearic acid.
 13. The method ofclaim 11, wherein the abuse-resistant opioid compound is represented byFormula IV:

wherein, R¹ is selected from the group consisting of hydroxy, alkoxy,and —OC(O)-alkoxy; R² is selected from the group consisting of hydroxyand —OC(O)R⁴; R³ and R⁴ are selected from the group consisting of—CHR⁵R⁶, —C_(a)H_(b), —C₂H₃R⁷R⁸, —C₂H₄NHC(O)C₂H₃R⁹R¹⁰,—C₂H₄NC(O)C₂H₃R¹¹R¹², —C₂H₄NC(O)CHR²³R²⁴, —C₂H₃CHR²⁹R³⁰,—C₂H₄NHC(O)(CH)₂C(O)OH, —C₂H₄C(O)OCHR³¹R³², —C₂H₄NHC(O)CHR³³R³⁴, and—C₃H₅R³⁵R³⁶; R⁵ is selected from the group consisting of hydroxy,—OC(O)-alkoxy; —NHC(O)CHR¹⁷R¹⁸, —NHC(O)C₂H₃R¹⁹R²⁰, —OC(O)CHR²¹R²²,4-methylimidazole, —OC(O)C₂H₄NH₂, —OC(O)C₂H₄NHC(O)CHR²⁵R²⁶,—OC(O)C₂H₃R²⁷R²⁸, —OC(O)(CH₂)₁₆CH₃, —OC(O)C₂H₄C(O)OH,—OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, —CH₂COOH, —OC(O)CH₃, —CHR³⁷R³⁸,—CH₂C(O)OCHR³⁹R⁴⁰, —OC(O)C₃H₅R⁴¹R⁴², —CH₂C(O)OC₂H₅,—OC(O)C₂H₄NHC(O)C₄H₇NH, —OC(O)C₄H₇NH, —OC(O)C₂H₃NHC(O)C₂H₃R⁴³R⁴⁴,—OC(O)C₂H₄CHR⁴⁵R⁴⁶, and —OC(O)C₂H₄NHC(O)C₃H₅R⁴⁷R⁴⁸; R⁶ is selected fromthe group consisting of alkyl, hydroxy, aryl, —CH₂COOH, —NHC(O)C₂H₄NH₂,—C(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, —C(O)(CH₂)₁₆CH₃, —CH₂C(O)CHR⁴⁹R⁵⁰,—CH₂C(O)OC₄H₉, —OC(O)CH₃, —OC(O)C₂H₄C(O)OH, —NHC(O)C₂H₄NHC(O)CHR⁵¹R⁵²,and —OC(O)(CH₂)₁₆CH₃; R⁷ is selected from the group consisting ofhydroxy, amino, —OC(O)CH₃, —NHC(O)CHR⁵³R⁵⁴, —OC(O)CHR⁵⁵R⁵⁶, and—OC(O)C₂H₃R⁵⁷R⁵⁸; R⁸ is selected from the group consisting of carboxyl,hydroxy, —C(O)OC₄H₉, —OC(O)CH₃, and —C(O)OCHR⁵⁹R⁶⁰; R⁹ is selected fromthe group consisting of hydroxy, carboxyl, —NHC(O)CHR⁶¹R⁶², and—C(O)OCHR⁶³R⁶⁴; R¹⁰, R¹², R²⁹, R³¹, R³⁵, R³⁹, R⁴², R⁴⁴, R⁴⁶, R⁴⁸, R⁵⁷,R⁵⁹, R⁶³, R⁶⁹, R⁷³R⁷⁵ are each independently carboxyl; R¹¹, R⁴³, R⁵²,R⁵³, R⁵⁶, R⁵⁸, R⁷⁰, R⁷⁷, R⁷⁹, R⁸⁴ are each independently hydroxy; R¹⁷,R²⁴, R³⁴ are each independently selected from the group consisting ofhydroxy, aryl, and alkyl; R¹⁸ is selected from the group consisting of—CH₂COOH and hydroxy; R¹⁹ and R²⁰ are each independently selected fromthe group consisting of hydroxy and carboxyl; R²¹ is selected from thegroup consisting of alkyl, aryl, substituted aryl, hydroxy, amino,—OC(O)CH₃, —NHC(O)CHR⁶⁷R⁶⁸, —NHC(O)C₂H₃CHR⁶⁹R⁷⁰, and —NHC(O)C₄H₇NH; R²²is selected from the group consisting of alkyl, hydroxy, amino,—NHC(O)CHR⁷¹R⁷², —CH₂COOH, —OC(O)(CH₂)₁₆CH₃, —OC(O)CH₃, —CH₂COOH,—(CH₂)₂COOH, —CH₂C(O)OC₄H₉, —CHR⁷³R⁷⁴, —NHC(O)C₄H₇NH,—OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, and —CHR⁷⁵R⁷⁶; R²³ is selected from thegroup consisting of hydroxy, aryl, —CH₂COOH, and—OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃; R²⁵ is selected from the group consisting ofalkyl, —C₂H₄C(O)OH, substituted aryl, and amino; R²⁶ is selected fromthe group consisting of alkyl, hydroxy, amino, substituted aryl,—NHC(O)CH₃, and —(CH₂)₂COOH; R²⁷ is selected from the group consistingof carboxyl, —NHC(O)CHR⁷⁷R⁷⁸, and —C(O)OC₄H₉; R²⁸ is selected from thegroup consisting of amino, hydroxy, carboxyl, and —OC(O)CH₃; R³⁰ is—NHC(O)CHR⁷⁹R⁸⁰; R³² is selected from the group consisting of aryl,—CH₂COOH, and alkyl; R³³ is selected from the group consisting of—CH₂COOH and hydroxy; R³⁶ is NHC(O)CHR⁸³R⁸⁴; R³⁷, R⁶¹, R⁷⁴ are eachindependently selected from the group consisting of hydroxy and—OC(O)CH₃; R³⁸ is selected from the group consisting of carboxyl and—C(O)OCHR⁸¹R⁸²; R⁴¹, R⁴⁵, and R⁴⁷ are each independently amino; R⁴⁰,R⁶², R⁶⁴ are each independently selected from the group consisting ofalkyl and aryl; R⁴⁹ and R⁷⁶ are each independently —OC(O)CH₃; R⁵⁰, R⁵¹,R⁵⁴, R⁵⁵, R⁶⁰, R⁷⁸, R⁸⁰, R⁸³ are each independently alkyl; R⁶⁷ isselected from the group consisting of alkyl and —NHC(O)CH₃; R⁶⁸ isselected from the group consisting of hydroxy and —(CH₂)₄NH₂; R⁷¹ isselected from the group consisting of hydroxy, —NHC(O)CH₃, and amino;R⁷² is selected from the group consisting of alkyl and —C₄H₈NH₂; R⁸¹ isselected from the group consisting of carboxyl, aryl, and —CH₂COOH; R⁸²is selected from the group consisting of alkyl, aryl, carboxyl, and—CH₂COOH; T is a pharmaceutically acceptable salt a is from 1 to 30; bis from 1 to 50; c is from 0 to 5; and d is from 0 to
 10. 14. A methodof preventing opioid abuse, comprising administering a therapeuticallyeffective amount of an abuse-resistant opioid compound to a subject inneed thereof, wherein the abuse-resistant opioid compound is representedby Formula I:O—X_(n)  (I) wherein, O is an opioid selected from the group consistingof oxycodone and oxymorphone; each X is an independent chemical moietythat is safe for human consumption and is selected from the groupconsisting of an amino acid, a dipeptide, an a-hydroxy acid, adicarboxylic acid, and a fatty acid; and n is from 1 to
 10. 15. Themethod of claim 14, wherein X comprises alanine, proline, carnosine,lactic acid, mandelic acid, malic acid, tartaric acid, succinic acid,citric acid, sorbic acid, oleic acid, or stearic acid.
 16. The method ofclaim 14, wherein the abuse-resistant opioid compound is represented byFormula IV:

wherein, R¹ is selected from the group consisting of hydroxy, alkoxy,and —OC(O)-alkoxy; R² is selected from the group consisting of hydroxyand —OC(O)R⁴; R³ and R⁴ are selected from the group consisting of—CHR⁵R⁶, —C_(a)H_(b), —C₂H₃R⁷R⁸, —C₂H₄NHC(O)C₂H₃R⁹R¹⁰,—C₂H₄NC(O)C₂H₃R¹¹R¹², —C₂H₄NC(O)CHR²³R²⁴, —C₂H₃CHR²⁹R³⁰,—C₂H₄NHC(O)(CH)₂C(O)OH, —C₂H₄C(O)OCHR³¹R³², —C₂H₄NHC(O)CHR³³R³⁴, and—C₃H₅R³⁵R³⁶; R⁵ is selected from the group consisting of hydroxy,—OC(O)-alkoxy; —NHC(O)CHR¹⁷R¹⁸, —NHC(O)C₂H₃R¹⁹R²⁰, —OC(O)CHR²¹R²²,4-methylimidazole, —OC(O)C₂H₄NH₂, —OC(O)C₂H₄NHC(O)CHR²⁵R²⁶,—OC(O)C₂H₃R²⁷R²⁸, —OC(O)(CH₂)₁₆CH₃, —OC(O)C₂H₄C(O)OH,—OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, —CH₂COOH, —OC(O)CH₃, —CHR³⁷R³⁸,—CH₂C(O)OCHR³⁹R⁴⁰, —OC(O)C₃H₅R⁴¹R⁴², —CH₂C(O)OC₂H₅,—OC(O)C₂H₄NHC(O)C₄H₇NH, —OC(O)C₄H₇NH, —OC(O)C₂H₃NHC(O)C₂H₃R⁴³R⁴⁴,—OC(O)C₂H₄CHR⁴⁵R⁴⁶, and —OC(O)C₂H₄NHC(O)C₃H₅R⁴⁷R⁴⁸; R⁶ is selected fromthe group consisting of alkyl, hydroxy, aryl, —CH₂COOH, —NHC(O)C₂H₄NH₂,—C(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, —C(O)(CH₂)₁₆CH₃, —CH₂C(O)CHR⁴⁹R⁵⁰,—CH₂C(O)OC₄H₉, —OC(O)CH₃, —OC(O)C₂H₄C(O)OH, —NHC(O)C₂H₄NHC(O)CHR⁵¹R⁵²,and —OC(O)(CH₂)₁₆CH₃; R⁷ is selected from the group consisting ofhydroxy, amino, —OC(O)CH₃, —NHC(O)CHR⁵³R⁵⁴, —OC(O)CHR⁵⁵R⁵⁶, and—OC(O)C₂H₃R⁵⁷R⁵⁸; R⁸ is selected from the group consisting of carboxyl,hydroxy, —C(O)OC₄H₉, —OC(O)CH₃, and —C(O)OCHR⁵⁹R⁶⁰; R⁹ is selected fromthe group consisting of hydroxy, carboxyl, —NHC(O)CHR⁶¹R⁶², and—C(O)OCHR⁶³R⁶⁴; R¹⁰, R¹², R²⁹, R³¹, R³⁵, R³⁹, R⁴², R⁴⁴, R⁴⁶, R⁴⁸, R⁵⁷,R⁵⁹, R⁶³, R⁶⁹, R⁷³, R⁷⁵ are each independently carboxyl; R¹¹, R⁴³, R⁵²,R⁵³, R⁵⁶, R⁵⁸, R⁷⁰, R⁷⁷, R⁷⁹, R⁸⁴ are each independently hydroxy; R¹⁷,R²⁴, R³⁴ are each independently selected from the group consisting ofhydroxy, aryl, and alkyl; R¹⁸ is selected from the group consisting of—CH₂COOH and hydroxy; R¹⁹ and R²⁰ are each independently selected fromthe group consisting of hydroxy and carboxyl; R²¹ is selected from thegroup consisting of alkyl, aryl, substituted aryl, hydroxy, amino,—OC(O)CH₃, —NHC(O)CHR⁶⁷R⁶⁸, —NHC(O)C₂H₃CHR⁶⁹R⁷⁰, and —NHC(O)C₄H₇NH; R²²is selected from the group consisting of alkyl, hydroxy, amino,—NHC(O)CHR⁷¹R⁷², —CH₂COOH, —OC(O)(CH₂)₁₆CH₃, —OC(O)CH₃, —CH₂COOH,—(CH₂)₂COOH, —CH₂C(O)OC₄H₉, —CHR⁷³R⁷⁴, —NHC(O)C₄H₇NH,—OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃, and —CHR⁷⁵R⁷⁶; R²³ is selected from thegroup consisting of hydroxy, aryl, —CH₂COOH, and—OC(O)(CH₂)₇(CH)₂(CH₂)₇CH₃; R²⁵ is selected from the group consisting ofalkyl, —C₂H₄C(O)OH, substituted aryl, and amino; R²⁶ is selected fromthe group consisting of alkyl, hydroxy, amino, substituted aryl,—NHC(O)CH₃, and —(CH₂)₂COOH; R²⁷ is selected from the group consistingof carboxyl, —NHC(O)CHR⁷⁷R⁷⁸, and —C(O)OC₄H₉; R²⁸ is selected from thegroup consisting of amino, hydroxy, carboxyl, and —OC(O)CH₃; R³⁰ is—NHC(O)CHR⁷⁹R⁸⁰; R³² is selected from the group consisting of aryl,—CH₂COOH, and alkyl; R³³ is selected from the group consisting of—CH₂COOH and hydroxy; R³⁶ is NHC(O)CHR⁸³R⁸⁴; R³⁷, R⁶¹, R⁷⁴ are eachindependently selected from the group consisting of hydroxy and—OC(O)CH₃; R³⁸ is selected from the group consisting of carboxyl and—C(O)OCHR⁸¹R⁸²; R⁴¹, R⁴⁵, and R⁴⁷ are each independently amino; R⁴⁰,R⁶², R⁶⁴ are each independently selected from the group consisting ofalkyl and aryl; R⁴⁹ and R⁷⁶ are each independently —OC(O)CH₃; R⁵⁰, R⁵¹,R⁵⁴, R⁵⁵, R⁶⁰, R⁷⁸, R⁸⁰, R⁸³ are each independently alkyl; R⁶⁷ isselected from the group consisting of alkyl and —NHC(O)CH₃; R⁶⁸ isselected from the group consisting of hydroxy and —(CH₂)₄NH₂; R⁷¹ isselected from the group consisting of hydroxy, —NHC(O)CH₃, and amino;R⁷² is selected from the group consisting of alkyl and —C₄H₈NH₂; R⁸¹ isselected from the group consisting of carboxyl, aryl, and —CH₂COOH; R⁸²is selected from the group consisting of alkyl, aryl, carboxyl, and—CH₂COOH; T is a pharmaceutically acceptable salt; a is from 1 to 30; bis from 1 to 50; c is from 0 to 5; and d is from 0 to 10.